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.

Suggestive Findings

Factor V Leiden thrombophilia should be suspected in individuals with the following clinical, laboratory, and family history findings:

• Clinical findings. A history of one or recurrent venous thromboembolism (VTE) manifesting as deep vein thrombosis (DVT) or pulmonary embolism (PE), especially at a young age and in the absence of strong risk factors for VTE
• Laboratory findings. Low activated protein C (APC) resistance on APC resistance qualitative and quantitative assays [Amiral et al 2017]
  Note: The assay is (1) cost effective with high sensitivity and specificity; (2) can detect pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another F5 pathogenic variant that causes factor V deficiency); (3) can suggest other causes for low APC such as other F5 variants (e.g., F5 Hong Kong and F5 Cambridge), protein S deficiency, elevated factor VIII, presence of lupus anticoagulant, exogenous hormone use, and pregnancy or the postpartum period [Douxfils et al 2023].
• Family history of first-degree relatives with one or more VTE events consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Molecular genetic testing is recommended in individuals who have [Konstantinides et al 2020, Arachchillage et al 2022, Middeldorp et al 2023]:

• Low APC resistance assay values to confirm the diagnosis and to distinguish factor V Leiden variant heterozygotes from homozygotes and pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another F5 pathogenic variant that causes factor V deficiency);
• Borderline APC resistance assay values to confirm the diagnosis;
• Received direct thrombin inhibitors or direct factor Xa inhibitors, which may interfere with the results of the APC resistance assay [Kadauke et al 2014];
• Positive lupus anticoagulant and prolonged baseline activated partial thromboplastin time (aPTT);
• VTE provoked by pregnancy or occurring post partum;
• VTE associated with the use of combined oral contraceptives;
• VTE at age ≤40 years, either spontaneous or associated with weak environmental risk factors and family history of at least one first-degree relative with VTE.

The value of factor V Leiden variant testing is not established in:

• Persons with a first unprovoked VTE who are planning to stop anticoagulation;
• Female relatives of persons with VTE or hereditary thrombophilia considering estrogen contraception or hormone replacement therapy (HRT);
• Female relatives of persons with VTE or hereditary thrombophilia contemplating prophylactic anticoagulation during pregnancy.

Factor V Leiden variant testing should not routinely be performed in:

• Adults with VTE provoked by major transient risk factors;
• Persons with arterial thrombosis;
• Women with unexplained pregnancy loss;
• Neonates and children with asymptomatic central venous catheter-related thrombosis;
• Asymptomatic adult family members of individuals known to have a factor V Leiden variant;
• Routine testing in unaffected individuals (e.g., during pregnancy or prior to use of oral contraceptives, HRT, or selective estrogen receptor modulators), in asymptomatic children, prenatal testing of the fetus, or newborn testing.

Establishing the Diagnosis

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 (factor V Leiden variant; see Table 1) on molecular genetic testing.

Molecular genetic testing approaches can include targeted analysis for the factor V Leiden variant or a multigene panel.

• Targeted analysis for F5 pathogenic variant c.1601G>A (p.Arg534Gln) can be performed first.
• A multigene panel that includes F5 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

Table 1.

Molecular Genetic Testing Used in Factor V Leiden Thrombophilia

Clinical Description

Additional Acquired Risk Factors for VTE

Additional acquired risk factors for VTE in factor V Leiden variant heterozygotes or homozygotes are summarized in Table 2.

Table 2.

Increased Risk of Thrombosis in Persons with the Factor V Leiden Variant and Additional Acquired Risk Factors

Malignancy. To what extent inherited thrombophilia increases the risk of VTE in persons with cancer remains controversial [Decousus et al 2007, Pabinger et al 2015]. Because malignancy is such a strong thrombotic risk factor, it may obscure the effect of mild thrombophilic disorders including factor V Leiden thrombophilia. Thrombophilia status was not considered in guidelines for prophylaxis and treatment of VTE in individuals with cancer [Farge et al 2013].

Combined oral contraceptive (COC) use substantially increases the relative risk for VTE in women heterozygous for the factor V Leiden variant [LaVasseur et al 2022]. The incidence of VTE in COC users with either the factor V Leiden variant or the F2 20210G>A variant ranged from 0.49 to 0.86/100 pill-years in heterozygotes or double heterozygotes, respectively [van Vlijmen et al 2011].

The supra-additive effect of both a factor V Leiden variant and use of COCs was confirmed in multiple studies in which the OR for VTE ranged from 11 to 41 [Wu et al 2005, Dayan et al 2011, Bergendal et al 2014, van Vlijmen et al 2016]. For women who are either homozygous for the factor V Leiden variant or double heterozygous for the factor V Leiden variant and the F2 20210G>A variant, the OR for VTE ranged from 17 to 110 [Mohllajee et al 2006, van Vlijmen et al 2016].

The thrombotic risk in COC users with the factor V Leiden variant is at least as high in women older than age 50 years as in younger users [Roach et al 2013]. However, since the incidence of VTE increases with age, the absolute risk for VTE in women older than age 50 years is much higher than in younger COC users.

Oral hormone replacement therapy (HRT) is associated with a two- to fourfold increased relative risk for VTE in healthy postmenopausal users of HRT compared to nonusers [Renoux et al 2010, Eisenberger & Westhoff 2014]. The risk increases with higher estrogen doses and may differ with the particular estrogen and progestin components [Renoux et al 2010, Canonico et al 2011, Smith et al 2014]. The risk of VTE is increased threefold in postmenopausal women with a factor V Leiden or F2 20210G>A variant than in HRT users without thrombophilia [Roach et al 2013].

Transdermal HRT. Multiple observational studies consistently found that transdermal HRT did not increase the risk of VTE [Canonico et al 2010, Sweetland et al 2012, ACOG 2013a]. There is also evidence that transdermal estrogen is associated with a lower thrombotic risk (HR 1.1, 95% CI 0.8-1.8) than oral estrogen (HR 1.7, 95% CI 1.1-2.8) in women with the factor V Leiden variant [Canonico et al 2010]. The risk for women with a prothrombotic variant (including the factor V Leiden variant) using transdermal estrogen was similar to that of women with a prothrombotic variant who were not using transdermal estrogen (OR 4.4, 95% CI 2.0 to 9.9 and OR 4.1, 95% CI 2.3 to 7.4, respectively) [Straczek et al 2005]. However, no prospective randomized trials have confirmed the safety of transdermal HRT in women with inherited thrombophilia. Among women with the factor V Leiden variant, the use of oral estrogen was associated with a fourfold increased risk for VTE over transdermal estrogen [Straczek et al 2005].

Prevalence

Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. The prevalence varies by population.

Heterozygosity for the factor V Leiden variant occurs in 3%-8% of the general United States and European populations. The highest heterozygosity rate is found in Europe. Within Europe, prevalence varies from 10%-15% in southern Sweden and Greece to 2%-3% in Italy and Spain [Kujovich 2011]. The factor V Leiden variant is extremely rare in Asian, African, and indigenous Australian populations [Kujovich 2011]. In the US, prevalence reflects the world distribution of the factor V Leiden variant [Ridker et al 1997, Kujovich 2011], which is present in 5.2% of Americans of European origin, 2.2% of Hispanic Americans, 1.2% of African Americans, 0.45% of Asian Americans, and 1.25% of Native Americans.

The frequency of homozygosity for the factor V Leiden variant is approximately 1:5,000.

The factor V Leiden variant is present in approximately 15%-20% of individuals with a first deep vein thrombosis and up to 50% of individuals with recurrent VTE or an estrogen-related thrombosis.

Evaluations Following Initial Diagnosis

To assess the risk for venous thromboembolism (VTE) in an individual found to have a factor V Leiden variant, the following are recommended:

• DNA analysis for prothrombin thrombophilia (F2 variant c.*97G>A, commonly known as 20210G>A)
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
• Serologic assays for anticardiolipin antibodies and anti-beta-2-glycoprotein 1 antibodies

For high-risk individuals (i.e., those with a history of recurrent VTE, especially at a young age, or those with strong family history of VTE at a young age), evaluation should also include assays of:

• Protein C activity
• Antithrombin activity
• Protein S activity or free protein S antigen

Note: Measurement of the following is NOT recommended:

• Plasma concentration of homocysteine, as no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
• MTHFR variants, as no clinical rationale for this testing exists
• Factor VIII and other clotting factor levels [Moll 2015]

Treatment of Manifestations

Prevention of Primary Manifestations

In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic individuals who are heterozygous for the factor V Leiden variant because the 1%-3% per year risk for major bleeding from warfarin is greater than the estimated less than 1% per year risk for thrombosis.

Because the initial thrombosis in 50% of factor V Leiden variant heterozygotes occurs in association with other circumstantial risk factors (see Table 2), a short course of prophylactic anticoagulation during exposure to hemostatic stresses may prevent some of these episodes. However, currently no evidence confirms the benefit of primary prophylaxis for asymptomatic factor V Leiden variant heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors.

Selected factor V Leiden variant heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in consensus guidelines [Kearon et al 2016, Kakkos et al 2021].

Surveillance

Individuals receiving long-term anticoagulation require periodic reevaluation of their clinical course 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 should avoid estrogen-containing contraception and hormone replacement therapy (HRT).

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

Asymptomatic women heterozygous for the factor V Leiden variant:

• Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
• Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
• Electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations and is not associated with higher thrombotic risk in healthy women [Morris & Talaulikar 2023].

Evaluation of Relatives at Risk

The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the F5 pathogenic variant c.1601G>A (p.Arg534Gln).

Note: The indications for family testing are sustained by low clinical evidence.

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. In particular, individuals with a first-degree relative with a factor V Leiden variant, no (or only minor) risk factors, and no history of VTE should not tested [Middeldorp et al 2023].

At-risk females (family history of recurrent VTE at a young age and/or known factor V Leiden thrombophilia) should avoid estrogen-containing contraception and HRT [Middeldorp et al 2023].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Factor V Leiden thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.

Individuals who are heterozygous for the factor V Leiden variant (F5 variant c.1601G>A [p.Arg534Gln]) have a slightly increased risk for venous thrombosis; individuals who are homozygous for the factor V Leiden variant have a much greater thrombotic risk (see Clinical Description, Homozygosity for the Factor V Leiden Variant). Many individuals with the factor V Leiden variant never develop thrombosis (see Clinical Description).

Risk to Family Members

Parents of a proband

• 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.
• More rarely, individuals with factor V Leiden thrombophilia are homozygous for the factor V Leiden variant, having inherited one factor V Leiden variant from each parent.
• Occasionally – because of the relatively high frequency of the factor V Leiden variant in the general population – one parent is homozygous for the factor V Leiden variant or both parents are heterozygous for the factor V Leiden variant.
• The family history of some individuals diagnosed with factor V Leiden thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize factor V Leiden thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous (or homozygous) for the factor V Leiden variant.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If one parent is heterozygous for the factor V Leiden variant, each sib of the proband is at a 50% risk of being heterozygous for the factor V Leiden variant.
• If one parent is homozygous for the factor V Leiden variant, each sib of the proband has a 100% chance of being heterozygous for the factor V Leiden variant.
• If both parents are heterozygous for the factor V Leiden variant, each sib of the proband 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.

Offspring of a proband

• 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.
• All children of an individual who is homozygous for the factor V Leiden variant will inherit the factor V Leiden variant from the proband. If the proband's reproductive partner is heterozygous for the factor V Leiden variant, each of their children has a 50% chance of being homozygous and a 50% chance of being heterozygous for the factor V Leiden variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: the family members of an individual who is heterozygous or homozygous for the factor V Leiden variant are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with factor V Leiden thrombophilia.
• See Pregnancy Management for review of prevention of thrombosis during pregnancy and the postpartum period.

Prenatal Testing and Preimplantation Genetic Testing

Once the factor V Leiden variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly in regard to testing for the factor V Leiden variant, which is common in the general population and is predisposing to, but not predictive of, thrombosis.

Molecular Pathogenesis

Factor V Leiden variant refers to missense variant c.1601G>A in F5, which encodes coagulation factor V, a key regulator in the coagulation cascade. Once activated, factor V functions as a cofactor that accelerates clot formation. Factor V is inactivated when cleaved by activated protein C (APC). The factor V Leiden variant, c.1601G>A (p.Arg534Gln), causes the substitution of glutamine for arginine at the Arg534 APC cleavage site, which is required for factor V inactivation by APC [Kujovich 2011].

Factor V with the Leiden variant is inactivated at an approximately tenfold slower rate than normal due to this amino acid change, resulting in less efficient APC cleavage. Factor V with the Leiden variant persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state, reflected by elevated levels of D-dimer, prothrombin fragment F1+2, and other activated coagulation markers [Martinelli et al 1996, Zöller et al 1996, Dahlbäck 2008, Kujovich 2011].

The factor V Leiden variant is frequent in the population (see Prevalence), leading to speculation of a survival advantage associated with the heterozygous state [Kujovich 2011].

Other F5 variants at APC cleavage sites, p.Arg334Thr (F5 Cambridge) and p.Arg334Gly, are not major risk factors for thrombosis, but may contribute when combined with other genetic or acquired risk factors.

Mechanism of disease causation. The lower inactivation rate of factor V with the Leiden variant results in increased thrombin generation [Kujovich 2011].

F5-specific laboratory technical considerations. Using legacy nomenclature, amino acid numbering begins 28 amino acids after the ATG transcription start site.

Table 3.

Notable F5 Pathogenic Variants

Author Notes

Prof Daniele Pastori, MD, PhD, FESC; Sapienza University of Rome
Email: [email protected]

Dr Danilo Menichelli, MD; Sapienza University of Rome
Email: [email protected]

Dr Emanuele Valeriani, MD; Sapienza University of Rome
Email: [email protected]

Prof Pasquale Pignatelli, MD, PhD; Sapienza University of Rome
Email: [email protected]

Contact Prof Daniele Pastori to inquire about review of F5 variants of uncertain significance.

Author History

Scott H Goodnight, MD; Oregon Health & Science University (1998-2004)
Jody L Kujovich, MD; Oregon Health and Science University (1998-2024)
Danilo Menichelli, MD (2024-present)
Daniele Pastori, MD, PhD, FESC (2024-present)
Pasquale Pignatelli, MD, PhD (2024-present)
Emanuele Valeriani, MD (2024-present)

Revision History

• 16 May 2024 (sw) Comprehensive update posted live
• 4 January 2018 (bp) Comprehensive update posted live
• 9 March 2010 (me) Comprehensive update posted live
• 12 February 2007 (me) Comprehensive update posted live
• 20 May 2004 (me) Comprehensive update posted live
• 18 June 2002 (me) Comprehensive update posted live
• 14 May 1999 (pb) Review posted live
• 29 December 1998 (jk) Original submission

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