Factor V Leiden Thrombophilia

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. It is unlikely that 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, fetal growth restriction, and placental abruption). The clinical expression of factor V Leiden thrombophilia is influenced by the following:

  1. The number of Leiden variants (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk)

  2. Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk

  3. Acquired thrombophilic disorders: antiphospholipid antibody (APLA) syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors

  4. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and advancing age

Diagnosis/testing: Factor V Leiden thrombophilia is suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep vein thrombosis (DVT) or pulmonary embolism, especially in women with a history of VTE during pregnancy or in association with use of estrogen-containing contraceptives, and in individuals with a personal or family history of recurrent thrombosis. The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1691G>A variant (referred to as the factor V Leiden variant in F5, the gene encoding factor V) in conjunction with coagulation tests such as the APC resistance assay.

Management: Treatment of manifestations: The first acute thrombosis is treated according to standard guidelines. The duration of oral anticoagulation therapy should be based on an assessment of the risks for VTE recurrence and anticoagulant-related bleeding.

Prevention of primary manifestations: In the absence of a history of thrombosis, long-term prophylactic anticoagulation is not routinely recommended for asymptomatic Leiden variant heterozygotes. A short course of prophylactic anticoagulation when circumstantial risk factors are present may prevent initial thrombosis in Leiden variant heterozygotes.

Surveillance: Periodic reevaluation of individuals on long-term anticoagulation to assess risks (bleeding) vs benefits.

Agents/circumstances to avoid:

  1. Women heterozygous for the Leiden variant and a history of VTE should avoid estrogen-containing contraception and HRT.

  2. Women homozygous for the Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT.

  3. While asymptomatic women heterozygous for the Leiden variant should be counseled to consider alternative forms of contraception and control of menopausal symptoms, those electing use of:

    1. Oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk.

    2. Short-term HRT for severe menopausal symptoms should avoid oral formulations.

Evaluation of relatives at risk: Although the genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing, the indications for testing of at-risk family members are unresolved. In the absence of evidence that early identification of the Leiden variant leads to interventions that can reduce morbidity or mortality, decisions regarding testing should be made on an individual basis. However, if the results are likely to affect management, clarification of Leiden variant status may be indicated in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age.

Genetic counseling: Factor V Leiden thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner. Homozygosity for the Leiden variant (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 reproductive partner of an affected individual needs to be evaluated before information regarding potential risks to sibs or offspring can be provided. Once the Leiden variant has been identified in a family member, prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible. 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 of this genetic change, which is common in the general population and is predisposing to, but not predictive of, thrombosis.

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  • Review