Factor V Leiden: all the answers

The term “factor V Leiden” refers by convention to a specific variant of the F5 gene, which codes for coagulation factor V. This variant, which at the nucleotide level is identified as G1691A, is quite frequent in the general population and is associated with the so-called “thrombophilia due to factor V Leiden deficiency” (also known as “hereditary resistance to activated protein C“). It should be noted immediately that the G1691A variant, although predisposing, is not predictive of thrombosis in all cases (some patients, in fact, remain asymptomatic).

Thrombophilia due to factor V Leiden deficiency is characterized by an increased risk of venous thromboembolism, especially deep vein thrombosis, most commonly in the legs. However, it should be noted that, from the numerous evidence acquired so far, it seems clear that the state of heterozygosity for the Leiden variant confers, at most, a modest effect on the risk of recurrent thromboembolism after the initial treatment of the first thrombosis. Homozygous individuals have instead a much higher thrombotic risk. As mentioned above, factor V Leiden is quite common in the general population: heterozygotes can be detected with a frequency of 1-4% in Europe (2-3% in Italy), while homozygotes are about 1 in every 5,000 people.

Regarding pregnancy, it is now clear that the factor V Leiden, both heterozygous and homozygous, does not actually represent a substantial risk factor for miscarriage or other adverse events of pregnancy (such as preeclampsia, reduced fetal growth or placental abruption).

The clinical manifestation of thrombophilia due to factor V Leiden deficiency is influenced by the following factors:

– Genotype: heterozygotes for the Leiden variant have only a slightly increased risk of venous thrombosis, while homozygotes have a much higher thrombotic risk.

– Coexistence of other thrombophilic diseases (genetic or acquired), which confer an additive risk for thrombosis.

– Presence of circumstantial risk factors such as pregnancy, central venous catheterization, travel, use of oral contraceptives, hormone replacement therapy, selective estrogen receptor modulators, obesity, trauma to the lower limbs and advanced age.

In asymptomatic patients (i.e. who have never had an episode of venous thrombosis), long-term prophylactic anticoagulant therapy is not indicated, but only short-term therapy in the event of an exposure to circumstantial risk factors (see above).

With particular reference to drugs or circumstances to avoid:

– Women heterozygous for the Leiden variant with a history of venous thromboembolism should avoid estrogen-based oral contraceptive therapy or hormone replacement therapy.

– women homozygous for the Leiden variant with or without a history of venous thromboembolism should avoid estrogen-based oral contraceptive therapy or hormone replacement therapy

– for asymptomatic heterozygous women it would still be advisable to evaluate alternative forms of contraception or control of menopausal symptoms. However, for asymptomatic heterozygous women who still prefer oral contraceptive therapy, it would be best to avoid third generation progestogens or other types of progestogens that confer a high thrombotic risk. For asymptomatic heterozygous women wishing to undergo hormone replacement therapy to control particularly severe menopausal symptoms, oral hormone replacement therapy should still be avoided.