Factor V Leiden Thrombophilia

Clinical characteristics: Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism. Thrombosis in unusual locations is less common. Factors that predispose to VTE in factor V Leiden thrombophilia include: the number of factor V Leiden variant alleles (homozygotes have a much greater thrombotic risk); family history of VTE; presence of coexisting genetic thrombophilic disorders; acquired thrombophilic disorders (e.g., antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders); and circumstantial risk factors (e.g., pregnancy, malignancy, central venous catheters, travel, combined oral contraceptive use and other combined contraceptives, oral hormone replacement therapy [HRT], obesity, leg injury, and advancing age).

Diagnosis/testing: The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in F5 on molecular genetic testing.

Management: Treatment of manifestations: The first acute venous thrombosis is treated according to current 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 factor V Leiden variant heterozygotes. A short course of prophylactic anticoagulation when transient risk factors are present may prevent initial thrombosis in heterozygotes.

Surveillance: Periodic reevaluation of individuals on long-term anticoagulation to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding. Factor V Leiden heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy.

Agents/circumstances to avoid: Women with a history of VTE who are heterozygous for the factor V Leiden variant and women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT. Women electing use of oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk. Women electing use of short-term HRT for severe menopausal symptoms should avoid oral formulations.

Evaluation of relatives at risk: The indications for testing of at-risk family members are unresolved. In the absence of evidence that early identification of the factor V Leiden variant leads to interventions that can reduce morbidity or mortality, decisions regarding testing should be made on an individual basis.

Pregnancy management: Women with thrombophilia should undergo individualized risk assessment. In women heterozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is not recommended for prevention of the first VTE. In homozygous and double heterozygous women (factor V Leiden and F2 20210G>A variants), antepartum and postpartum prophylactic anticoagulation is suggested to prevent a first VTE.

Genetic counseling: Factor V Leiden thrombophilia is inherited in an autosomal dominant manner. Individuals who are heterozygous for the factor V Leiden variant have a slightly increased risk for VTE; individuals who are homozygous for the factor V Leiden variant have a much greater thrombotic risk. Many individuals with the factor V Leiden variant never develop thrombosis. Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant. Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband; if the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.