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Factor V Leiden Thrombophilia.


Kujovich JL.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
1999 May 14 [updated 2010 Mar 9].



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 venous 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 a heterozygous factor V Leiden mutation has at most a modest effect on recurrence risk after initial treatment of a first VTE. Heterozygosity for factor V Leiden is associated with a two- to threefold increase in relative risk for pregnancy loss, and possibly other pregnancy complications such as preeclampsia, fetal growth retardation, and placental abruption. The clinical expression of factor V Leiden thrombophilia is influenced by: The number of factor V Leiden alleles (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk); Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk; Acquired thrombophilic disorders: antiphospholipid antibodies, hyperhomocysteinemia, high factor VIII levels, malignancy; and Circumstantial risk factors: travel, central venous catheters, pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, advancing age, and surgery.


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 oral contraceptive use, and in individuals with a personal or family history of recurrent thrombosis. The diagnosis of factor V Leiden thrombophilia is made either using a coagulation screening test or by DNA analysis of F5, which encodes the factor V protein. The term "factor V Leiden" refers to the specific G-to-A substitution at nucleotide 1691 in the gene for factor V that predicts a single amino-acid replacement (Arg506Gln) at one of three APC cleavage sites in the factor Va molecule.


Treatment of manifestations: The first acute thrombosis is treated according to standard guidelines (initial course of intravenous unfractionated heparin or low molecular-weight heparin and initiation of warfarin [except during pregnancy]). The duration of oral anticoagulation therapy is debated. Long-term oral anticoagulation is considered (1) in those with recurrent VTE, multiple thrombophilic disorders, or coexistent circumstantial risk factors and (2) in factor V Leiden homozygotes. 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 heterozygotes. A short course of prophylactic anticoagulation when circumstantial risk factors are present may prevent initial thrombosis in factor V Leiden heterozygotes. Prevention of secondary complications: Enoxaparin prophylaxis in women heterozygous for factor V Leiden who have a history of recurrent pregnancy loss may increase the likelihood of a favorable pregnancy outcome. Surveillance: Periodic reevaluation of individuals on long-term anticoagulation to assess risks (bleeding) vs. benefits. Agents/circumstances to avoid: Oral contraceptives and HRT (homozygous women with or without prior VTE); oral contraceptives, especially third-generation formulations, are also discouraged in asymptomatic heterozygous women. Evaluation of relatives at risk: Molecular genetic testing can establish the genetic status of asymptomatic at-risk family members; however, the indications for family testing are unresolved. Clarification of factor V Leiden allele status may be useful in at-risk relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. Asymptomatic factor V Leiden heterozygotes and homozygotes should be aware of the signs and symptoms of VTE that require immediate medical attention and the potential need for prophylactic anticoagulation in high-risk circumstances.


Heterozygosity for the factor V Leiden allele and the associated risk for venous thrombosis are inherited in an autosomal dominant manner. Homozygosity for the factor V Leiden allele 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. While technically possible, prenatal testing does not seem relevant for this complex disorder, in which the genetic change is common in the general population and is predisposing to, but not predictive of, thrombosis.

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