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 in the F5 gene. It does not discuss indications for testing, and it is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately in UpToDate [1]. (See 'UpToDate topics' below.)

OVERVIEW OF CLINICAL IMPLICATIONS

How to read the report — All of these names refer to the same variant (point mutation) in the F5 gene and the corresponding change to the factor V protein [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 for genetic testing (table 1).

The pathogenicity of FVL as a risk factor for venous thromboembolism (VTE) is well established. Other thrombophilic variants in the F5 gene are extremely rare.

Clinical significance (VTE risk) — FVL is a point mutation in the F5 gene, which encodes factor V (factor five) in the coagulation cascade. FVL shifts the balance towards clotting, as it renders factor Va resistant to inactivation by activated protein C. The inheritance pattern is autosomal dominant. (See "Factor V Leiden and activated protein C resistance", section on 'Biology of factor V and protein C'.)

●Heterozygosity for FVL is very common among White individuals (prevalence, approximately 5 percent). Approximately 90 percent of these individuals are unaware that they carry the variant and will never develop VTE. Heterozygosity for FVL confers an increased risk for VTE of approximately threefold to fourfold. Common sites of thrombosis include deep veins of the legs (deep vein thrombosis [DVT]) and pulmonary embolism (PE); less common sites include cerebral and portal veins. (See "Factor V Leiden and activated protein C resistance", section on 'Epidemiology'.)

●Homozygosity for FVL and compound heterozygosity for FVL plus another thrombophilia variant are uncommon and carry a higher risk of VTE than FVL heterozygosity (table 2). We do not routinely test for other thrombophilias in asymptomatic individuals with FVL, 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'.)

FVL has also been linked to pregnancy morbidity such as recurrent fetal loss, but the association is controversial and use of antithrombotic agents does not increase the chance of a live birth; recommendations are presented separately. (See 'Pregnancy morbidity' below and "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

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. (See 'Other VTE risk factors' below.)

Other VTE risk factors — Other major risk factors for VTE include:

●Personal history of VTE

●Family history of VTE

●Acquired VTE risk factors (estrogen-containing medications, pregnancy, immobility, trauma, surgery, acute or chronic medical illnesses [eg, antiphospholipid syndrome], cancer, and certain cancer therapies)

These and other risk factors are discussed separately. (See "Overview of the causes of venous thrombosis in adults".)

ASYMPTOMATIC INDIVIDUALS (NO PRIOR VTE)

VTE risk reduction — The absolute risk of venous thromboembolism (VTE) is increased to a small extent with heterozygosity for factor V Leiden (FVL) and increased somewhat more (but still low, likely <1 percent annually) in individuals with homozygosity for FVL or compound heterozygosity for FVL plus another thrombophilic variant (table 2), along with factors besides F5 genotype (see 'Other VTE risk factors' above). These should be considered when determining the risk reduction strategy for every patient.

Our approach to VTE risk reduction in heterozygous individuals with FVL is similar to the general population, with differences summarized in the figure (algorithm 1) and discussed in detail separately. (See "Factor V Leiden and activated protein C resistance", section on 'Management'.)

●Surgery – We are more likely to use prophylactic anticoagulation for certain surgeries. (See "Factor V Leiden and activated protein C resistance", section on 'Surgery'.)

●Airline and other travel – FVL alone is not considered an indication for pharmacologic prophylaxis. Risk reduction is discussed separately. (See "Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers".)

●Exogenous estrogens – (See 'Hormonal medications' below.)

●Pregnancy – (See 'Pregnancy' below.)

The table summarizes management implications (table 3).

Approaches to VTE risk reduction in individuals who are homozygous for FVL or compound heterozygous for FVL and another thrombophilia variant are summarized in the linked topic reviews.

Hormonal medications — Medications that contain estrogens can increase the risk of VTE; these include:

●Estrogen-containing contraceptives, used for any reason (birth control, acne, dysmenorrhea).

●Regimens for assisted reproduction therapy (ART).

●Menopausal hormone therapy (MHT), especially systemic; transdermal MHT and tibolone do not increase the risk of VTE.

●Oral estradiol is associated with a very low VTE risk increase.

●Some feminizing hormonal regimens for transgender women [3].

●Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are associated with a modest risk increase of VTE.

●Vaginal contraceptive ring increases the risk of VTE to a similar extent as combined oral contraceptives.

●Therapeutic dose progestogen-only increases the risk of VTE (injectable contraceptives).

Hormone medications that do not increase the risk of VTE include:

●Transdermal estrogen do not appear to increase VTE risk.

●Low-dose progesterone-only contraception, including the desogestrel-containing intrauterine device (IUD), subcutaneous implant, and "mini-pill" do not increase VTE risk.

●Testosterone does not increase VTE risk.

The table summarizes the magnitude of risk with different thrombophilias and different hormonal medicines (table 4).

The following individuals should avoid (or carefully consider risks and benefits for) hormonal therapies that increase VTE risk:

●FVL heterozygous with a personal history of VTE, unless concomitant anticoagulation is used

●FVL heterozygous with a strong family history of VTE

●FVL heterozygous with a major acquired thrombophilia such as cancer or immobilization

●Homozygous for FVL

●Compound heterozygous for FVL and another thrombophilia variant

If risk is high and another option is unavailable, such as with ART in an individual with one of the above risk profiles, pharmacologic thromboprophylaxis could be considered.

For individuals who are heterozygous for FVL and do not have a personal history of VTE, the decision to use or not to use these therapies depends on a personalized risk-benefit calculation that considers the reason for taking the medication and whether alternatives are available. As an example, we generally avoid estrogen-containing contraceptives when other forms of birth control, acne treatments, and/or approaches to dysmenorrhea are available. If an oral contraceptive is used, we select one with a low estrogen dose and a second-generation progestogen. For MHT, which is generally used in older individuals (older age increases baseline VTE risk), prudent prescribing is warranted, and we generally prefer a transdermal formulation rather than an oral regimen. (See 'Clinical significance (VTE risk)' above.)

Recommendations regarding when to avoid these medications in individuals with FVL and possible alternatives are presented in separate topic reviews.

●Contraceptive counseling – (See "Contraception: Counseling regarding inherited thrombophilias".)

●Acne – (See "Acne vulgaris: Management of moderate to severe acne in adolescents and adults".)

●Dysmenorrhea – (See "Primary dysmenorrhea in adolescents" and "Dysmenorrhea in adult females: Treatment".)

●MHT – (See "Treatment of menopausal symptoms with hormone therapy", section on 'Route'.)

Pregnancy — Pregnancy is a hypercoagulable state, with VTE risk highest in the six weeks postpartum. Although this risk is further increased in individuals with FVL (table 4), 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) and discussed separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)

PEOPLE WITH VTE — 

The choice of anticoagulant is not affected by factor V Leiden (FVL).

In some circumstances, treatment duration may be affected in individuals who are homozygous for FVL or compound heterozygous for FVL and another thrombophilia variant, depending on the circumstances of the venous thromboembolism (VTE).

Following a first episode of VTE provoked by a hormonal risk factor such as oral contraceptives, pregnancy, or the postpartum period, the presence of heterozygous FVL may justify considering indefinite duration anticoagulation in selected individuals [4]. (See "Factor V Leiden and activated protein C resistance", section on 'Patients with VTE' and "Venous thromboembolism: Initiation of anticoagulation".)

PREGNANCY MORBIDITY — 

Preeclampsia does not appear to be more common in individuals with factor V Leiden (FVL). It is unclear whether FVL increases the risk of early or late pregnancy loss, with most prospective studies not finding an association.

In individuals with recurrent miscarriage and FVL, low molecular weight heparin (LMWH) did not increase live birth rates [5]. This supports the practice of not testing for FVL or other inherited thrombophilias in individuals with pregnancy loss; rather, other causes of pregnancy loss may be considered. (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 factor V Leiden (FVL) is controversial and may not be indicated, especially if the family history is negative for venous thromboembolism (VTE). Risks and benefits of testing should be considered. For those with questions, referral to a thrombosis specialist or genetic counselor may be helpful.

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 estrogen-containing medication, 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 "Hereditary thrombophilia testing in adults without VTE".)

•Contraception – (See "Contraception: Counseling regarding 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: Preincision 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".)