Gene test interpretation: Factor V Leiden

INTRODUCTION — This monograph discusses the interpretation and possible interventions based on the results of genetic testing that reveals the factor V Leiden (FVL) variant. It does not discuss the indications for testing, and it is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately in UpToDate [1]. (See 'UpToDate topics' below.)

OVERVIEW OF CLINICAL IMPLICATIONS

How to read the report — All of the following refer to the same variant (point mutation) in the F5 gene [2]:

●Factor V Leiden (FVL)

●Factor V p.Arg534Gln or R534Q (previously designated p.Arg506Gln or R506Q) – Protein sequence change

●F5 c.1601G>A (previously designated c.1691G>A) – DNA sequence change

The checklist provides caveats related to genetic testing (table 1).

FVL is typically the only variant tested in the F5 gene (other thrombophilic variants in F5 are extremely rare), and its pathogenicity as a risk factor for venous thromboembolism (VTE) is well established. The magnitude and clinical significance are discussed below.

Clinical significance (VTE risk) — The FVL variant is a point mutation in the F5 gene, which encodes factor V in the coagulation cascade. FVL shifts the balance towards clotting, resulting in increased VTE risk. (See "Factor V Leiden and activated protein C resistance", section on 'Biology of factor V and protein C'.)

Heterozygosity for FVL confers an increased risk for VTE of approximately fourfold to fivefold (table 2). Common sites of thrombosis include deep veins of the legs (deep vein thrombosis [DVT]) and pulmonary emboli (PE); less common sites include cerebral and portal veins.

Homozygosity for FVL or compound heterozygosity (for FVL plus another thrombophilia variant) are infrequent and carry a higher risk. We do not routinely test for other variants in asymptomatic individuals, but many individuals who have had thrombophilia testing will have this information available. (See "Factor V Leiden and activated protein C resistance", section on 'Risk of initial VTE'.)

Heterozygosity for FVL is very common in White populations (approximately 5 percent). The vast majority of these individuals (approximately 90 percent) are unaware that they carry the variant and will never develop VTE. (See "Factor V Leiden and activated protein C resistance", section on 'Epidemiology'.)

The tested individual should be counseled that VTE risk depends on many inherited and acquired risk factors, and risk may be increased despite a negative test for FVL.

Other major risk factors include (see "Overview of the causes of venous thrombosis"):

●Prior personal history of VTE

●Other thrombophilic variants (table 2)

●Acquired VTE risk factors (estrogen therapy, pregnancy, immobility, trauma, surgery, acute or chronic medical illness)

●Family history of VTE, especially if unprovoked

An association between FVL and early pregnancy morbidity is controversial. (See 'Pregnancy morbidity' below.)

ASYMPTOMATIC INDIVIDUALS (NO PRIOR VTE)

VTE risk reduction — The risk of a first venous thromboembolism (VTE) is determined by many factors besides F5 genotype. These should be considered when determining the risk reduction strategy for every patient, regardless of whether they carry the FVL variant. (See 'Clinical significance (VTE risk)' above.)

Our approach to VTE risk reduction in FVL heterozygous individuals is similar to the general population, with the following differences:

●We are more likely to use prophylactic anticoagulation for certain surgeries. (See 'Surgery' below.)

●We often advise avoidance of exogenous estrogens. If contraception is used, we encourage alternative methods (progestin-releasing intrauterine systems, progestin-only oral agents, or nonhormonal methods). We encourage non-estrogen alternatives for dysmenorrhea (eg, nonsteroidal antiinflammatory drugs [NSAIDs]) or acne (eg, topical therapies). (See 'Estrogen-containing contraceptives' below.)

●We may use anticoagulation during pregnancy and postpartum if other risk factors are present. (See 'Pregnancy' below.)

This approach is illustrated in the table (table 3) and algorithm (algorithm 1).

VTE risk is increased in individuals who are homozygous for FVL or compound heterozygous for FVL and another inherited thrombophilia (table 4). This still translates to a relatively low overall risk (<1 percent per year), and we generally do not chronically anticoagulate these individuals. However, anticoagulation may be considered if there is a very strong family history of VTE. (See "Factor V Leiden and activated protein C resistance", section on 'FVL homozygous carriers'.)

Surgery — Surgery confers increased VTE risk independent of other risk factors, and FVL may further increase this risk.

We generally treat individuals with FVL as a high-risk group when making decisions about postoperative VTE prophylaxis, and when postoperative VTE prophylaxis is considered, we are more likely to use prophylactic anticoagulation rather than other modalities (aspirin or intermittent pneumatic compression alone). FVL does not affect the choice or dosing of anticoagulant.

Supporting evidence, anticoagulant dosing, and other recommendations are presented separately. (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Estrogen-containing contraceptives — Estrogen-containing contraceptives carry an increased risk of VTE independent of other risk factors, and the risk is significantly increased by the FVL variant (table 4). However, avoiding oral contraceptives must be balanced with the risk of unintended pregnancy, which also increases VTE risk.

●We avoid estrogen-containing contraceptives in individuals with the following:

•Homozygosity for FVL

•FVL plus another thrombophilia (table 2)

•Heterozygosity for FVL and personal history of VTE

•Heterozygosity for FVL and positive family history of VTE in a relative with FVL

●Alternatives to estrogen-containing contraceptives are favored for FVL heterozygous individuals with a negative personal and family history of VTE. However, an estrogen-containing contraceptive may be reasonable if other VTE risk factors are absent. If an oral estrogen-containing contraceptive is used, we use a pill with a low estrogen dose. (See "Contraception: Counseling for women with inherited thrombophilias", section on 'Choice of estrogen-progestin oral contraceptive'.)

Supporting evidence and contraceptive recommendations are presented separately. (See "Contraception: Counseling for women with inherited thrombophilias".)

Similar considerations apply when use of a hormonal contraceptive is considered for other indications such as treatment of acne or dysmenorrhea. (See "Dysmenorrhea in adult females: Treatment" and "Acne vulgaris: Management of moderate to severe acne in adolescents and adults", section on 'Oral hormonal therapies'.)

Pregnancy — Pregnancy is a hypercoagulable state, with VTE risk highest in the six weeks postpartum. This risk is further increased in individuals with FVL (table 4), although the increase by itself is generally not considered sufficient to justify anticoagulation.

Our approach to primary VTE prophylaxis is summarized in the table (table 5).

●For individuals without a prior VTE who are heterozygous for FVL, management is similar to the general population; we do not routinely provide prophylactic anticoagulation. Anticoagulation may be appropriate for selected individuals based on additional risk factors such as a strong family history of VTE, immobility, cancer, or surgery.

●For individuals without a prior VTE who are homozygous for FVL or heterozygous for FVL and another thrombophilia variant, we generally use intermediate dose or low dose heparin antepartum and intermediate dose heparin postpartum.

●For individuals who are heterozygous for FVL and have a cesarean birth, we provide two weeks of postpartum anticoagulation in addition to standard pneumatic compression while in the hospital.

Supporting evidence is presented separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)

Considerations for individuals with prior VTE or early pregnancy morbidity are discussed below. (See 'People with VTE' below and 'Pregnancy morbidity' below.)

Airline travel — Airline travel is associated with a small increased risk of VTE, especially with longer flights (>4 to 6 hours).

For healthy people who are traveling by airplane for >4 hours, we typically recommend frequent ambulation (every one to two hours) and/or calf and thigh muscle stretching. For individuals who place a high value on reducing VTE risk, we suggest below-the-knee graduated compression stockings.

Some individuals may ask about the value of taking low-dose aspirin. We do not recommend this, given the lack of supporting data for its benefit. (See "Factor V Leiden and activated protein C resistance", section on 'Asymptomatic individuals' and "Prevention of venous thromboembolism in adult travelers".)

PEOPLE WITH VTE — For individuals with venous thromboembolism (VTE), the presence of FVL generally does not affect management decisions regarding anticoagulation, choice of anticoagulant, or duration of therapy (algorithm 1). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Epidemiology and pathogenesis of acute pulmonary embolism in adults".)

An exception is homozygosity for FVL or double heterozygosity for FVL and another thrombophilia variant, which is considered high risk and generally is an indication for indefinite anticoagulation following a first VTE.

PREGNANCY MORBIDITY — It is unclear whether FVL increases the risk of early or late pregnancy loss, with most prospective studies not finding an association.

Preeclampsia does not appear to be more common with FVL.

Individuals with early or late pregnancy loss who are found to have FVL should be evaluated by their obstetrician to determine the likely cause(s). (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk' and "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology".)

CONSIDERATIONS FOR RELATIVES — Routine testing of first-degree relatives of an individual with FVL is controversial and may not be indicated, especially if the family history is negative for venous thromboembolism (VTE). For those with questions, referral to a hematologist or genetic counselor may be helpful.

Individuals with FVL should share this information with their first-degree relatives, who can discuss the risks and benefits of knowing their FVL status with their own clinicians and individualize decisions about whether to be tested.

We are most likely to find value in testing at-risk relatives of individuals with FVL who have a strong personal or family history of VTE, relatives considering use of an estrogen-containing contraceptive, and/or siblings of those with homozygosity for FVL or compound heterozygosity for FVL plus another inherited thrombophilia. (See "Factor V Leiden and activated protein C resistance", section on 'Post-diagnosis testing and testing of first-degree relatives'.)

RESOURCES

UpToDate topics

●Inherited thrombophilias:

•Clinical implications of FVL – (See "Factor V Leiden and activated protein C resistance".)

•Screening in asymptomatic individuals – (See "Screening for inherited thrombophilia in asymptomatic adults".)

•Contraception – (See "Contraception: Counseling for women with inherited thrombophilias".)

•Pregnancy – (See "Inherited thrombophilias in pregnancy".)

●Venous thromboembolism (VTE) prophylaxis:

•Hospitalization – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

•Orthopedic surgery – (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

•Other surgeries – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

•Pregnancy – (See "Venous thromboembolism in pregnancy: Prevention".)

•Cesarean delivery – (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Thromboembolism prophylaxis'.)

●Genetics concepts:

•Terminology – (See "Genetics: Glossary of terms".)

•Genetic testing – (See "Genetic testing".)

•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)