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Factor V Leiden Mutation

Editor: Amy E. Schmidt Updated: 4/8/2023 4:13:42 PM


Factor V Leiden is a point mutation of factor V, resulting in an elimination of the cleavage site in factor V and factor Va. This genetic defect leads to an increased risk of thrombosis, especially in homozygous or pseudo-homozygous factor V Leiden mutations. Many individuals with the mutation will never develop a venous thrombotic event (VTE). The decision about VTE risk reduction (both primary and secondary and prevention of recurrence) requires a great deal of clinical acumen, given that most people who carry the mutation will never have VTE.


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Normally, factor V synthesis principally occurs in the liver. Thrombin activates factor V, and once activated, it will convert prothrombin to thrombin. Activated protein C, one of the principal physiologic inhibitors of coagulation, degrades factor V. In the presence of what is called thrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and the action of protein C are important determinants in the negative feedback loop through which thrombin limits its activation.

Factor V Leiden is an autosomal dominant genetic condition that exhibits incomplete penetrance, meaning that not every person with the mutation will develop the disease. 

Factor V Leiden, also known as factor VR506Q and factor V Arg506 Gln, results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506). This abolishes the Arg506 cleavage site for activated protein C in Factor V and Va.[1] Factor V Leiden increases the risk of thrombosis as activated protein C, a natural anticoagulant, can not bind and inactivate factor V as there is a mutation in the binding site on factor V for activated protein C. Therefore, as factor V is not inactivated, it continues to be active and increases thrombosis risk.


Heterozygosity of the factor V Leiden mutation is the most common inherited thrombophilia in the unselected White population (prevalence, approximately 1% to 5%) and is considered the most common inherited thrombophilia in individuals with venous thromboembolism (prevalence of roughly 10% to 20%).[2] Heterozygosity of this genetic mutation increases the lifetime risk of thrombosis by about 7-fold, while homozygosity (which is rare) increases the risk by approximately 20-fold. Despite the increase in the risk of VTE, there is no clinical evidence that heterozygosity of factor V Leiden increases overall mortality.


Factor V Leiden results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691) that would lead to the replacement of arginine with glutamine at amino acid 506. This abolishes the Arg506 cleavage site for activated protein C in factor V and factor Va. The consequences are enhancing the procoagulant role of factor Va and the reduced anticoagulant role of factor V.[1]

History and Physical

The primary clinical manifestation of the factor V Leiden mutation is the risk for venous thromboembolism (VTE). However, the most common finding in individuals with factor V Leiden is a laboratory-only abnormality. Only a small percentage of individuals with factor V Leiden will develop VTE in their lifetime, with an approximate risk of 5% for factor V Leiden heterozygotes in the general population and up to 20% in thrombophilic families.

Venous Thromboembolism

  • The most common site of VTE is deep vein thrombosis (DVT) and pulmonary embolism (PE), but other sites, including superficial veins of the legs or cerebral, portal, and hepatic veins, may be involved.[3]
  • Isolated PE is a less common presentation. Without evidence of DVT, factor V Leiden patients can still present with PE. But this is a less common presentation of VTE in individuals with factor V Leiden compared with the general population, a phenomenon called the factor V Leiden paradox.[4]  
  • Cerebral vein thrombosis can occur in factor V Leiden individuals, especially in patients using oral contraceptive pills. Studies have shown that factor V Leiden can be associated with an increased risk of Budd-Chiari syndrome.[5]

Arterial Thromboembolism

  • The association between factor V Leiden and arterial thromboembolism remains controversial, and it is likely to be small if present.
  • Myocardial infarction: Studies have shown a modest increase in the risk of coronary artery disease in patients with factor V Leiden. It has been observed that the factor V Leiden mutation is associated with an increased risk of stroke, especially in women, smokers, and younger individuals.[6]

Pregnancy and Postpartum Thromboembolism Risk

  • Thromboembolism affects 1.2 of every 1000 deliveries.[7] Increased morbidity and mortality are reported with pregnancy-associated VTE for women [8][9]. However, based on current clinical evidence, inherited thrombophilias like factor V Leiden are neither considered risk factors for recurrent pregnancy losses nor implicated in affecting obstetrical outcomes.[10]
  • Women with factor V Leiden and other inherited thrombophilia with or without a family history of VTE are at increased risk of VTE and VTE-related complications during pregnancy. 


Testing for thrombophilia conditions in patients diagnosed with the first episode of DVT/PE is being discouraged according to the American Society of Hematology (ASH) guidelines as it is expensive with no clinically meaningful benefit.

Testing for factor V Leiden is indicated for individuals with venous thromboembolism, especially if:

  • VTE occurs at a young age, generally speaking, less than 50 yrs of age
  • Atypical sites of clotting like visceral vein thromboses like an ovarian vein, portal vein, or renal vein thrombosis 
  • Unexplained arterial thrombosis
  • Significant family history of thrombophilia
  • In a hospitalized patient developing VTE despite being on prophylactic anticoagulation with no other definite explanation for VTE 
  • Unexplained recurrent deep venous thrombosis/PE

Testing usually is not performed in individuals with a first episode, especially if it is provoked or if it occurs in people who are older than 50 years of age.

Factor V Leiden can be diagnosed by mutation analysis (genetic testing) or using a functional coagulation test for APC resistance.

  • Genetic testing is indicated for those with a family history of factor V Leiden. It is also preferred for members of a thrombophilic family, patients with antiphospholipid syndrome, or those who need to be on an anticoagulant. Individuals with a positive functional assay for APC resistance should have genetic testing to confirm a diagnosis.[11]
  • Mutation testing: Polymerase chain reaction methods can detect factor V Leiden mutation. The DNA from individuals without the mutation would be 'cut' by a restriction enzyme. In contrast, it will not cut DNA in patients with factor V Leiden mutation resulting in a different banding pattern on a DNA gel.[12]
  • Functional APC resistance assays: These tests cost less than genetic testing, but in rare cases, they can give a misleading, falsely normal result, especially in individuals on therapy with direct thrombin inhibitors or factor Xa inhibitors, as well as in the presence of a lupus anticoagulant.

Treatment / Management

Management of venous thromboembolism in people with factor V Leiden mutation is the same as that of the general population, and factor V Leiden mutation will not affect the decision about which anticoagulant one should use. The choice of anticoagulant is based on some factors like patient preference, adherence to therapy, the severity of thrombosis, and drug interactions. 

Generally, direct oral anticoagulants (DOAC) are usually used for patients with typical VTE presentations. Warfarin is preferred if there is a concern about adherence or for those who present with a submassive/massive pulmonary embolism who would benefit from maintaining INR at the high end of the therapeutic range.

The duration of VTE treatment is not different between factor V Leiden and the general population, and it depends on the risk of recurrent VTE. It is highly recommended that one continue indefinite anticoagulation for unprovoked, life-threatening venous thromboembolism, VTE at an unusual location or if it is recurrent.[13](B3)

Individuals with factor V Leiden homozygous mutation who undergo surgery should be treated as a high-risk group and receive prophylactic anticoagulation.

Differential Diagnosis

The differential diagnosis for deep vein thrombosis (DVT) includes the following:

Inherited Thrombophilia

  • Prothrombin G20210A mutation
  • Protein S deficiency 
  • Protein C deficiency
  • Antithrombin (AT) deficiency


  • Malignancy
  • Trauma/surgery
  • Pregnancy or use of oral contraceptives
  • Immobilization/obesity
  • Nephrotic syndrome
  • Antiphospholipid syndrome 
  • Paroxysmal nocturnal hemoglobinuria
  • Myeloproliferative disorders
  • Heart failure 
  • Severe liver disease.cirrhosis
  • Medications like tamoxifen, thalidomide, or lenalidomide


A proportion of the population with factor V Leiden will suffer from venous thrombosis. Thromboembolism, including pulmonary embolism, carries significant morbidity and mortality. However, despite the increase in the risk of VTE, there is no evidence that heterozygosity to factor V Leiden increases overall mortality.

Deterrence and Patient Education

Patient counseling and education include emphasizing specific aspects of a healthy lifestyle to improve prognosis.

  • Maintain a healthy weight, and lose weight if necessary.
  • Eat a healthy diet.
  • Get at least 2.5 hours of exercise per week. Walking is a good choice, but other activities, such as swimming, cycling, running, or playing tennis or team sports, are also good choices.
  • Do not smoke since it increases the risk of blood clots. Clinicians can assist with stop-smoking programs and medicines to improve the patient's chances of quitting permanently.

Pearls and Other Issues

Pertinent to factor V Leiden, it is essential to understand the relative risk of VTE risk compared to other thrombophilia conditions that help to guide management decisions. This risk is depicted in the below format for easy understanding.

Thrombophilia Condition A relative Increase in the Risk of Thrombosis
Factor V Leiden heterozygous 4.9 fold (3-8 fold) 
Factor V Leiden homozygous 16 fold
Factor V Leiden with other thrombophilia conditions like a prothrombin gene mutation 20 fold
Protein C deficiency 7 fold

Protein S deficiency

7 fold 
Antithrombin III deficiency 16 fold (up to 20 fold)
Prothrombin gene mutation, heterozygous 3.8 fold

So a patient having conditions like heterozygous factor V Leiden mutation, heterozygous prothrombin gene mutation, protein C, and protein S deficiency do not require lifetime anticoagulation. Thus patients with these thrombophilia conditions, management is no different than the management guidelines of the general population. Per ASH guidelines, 3 to 6 months of anticoagulation is recommended for the first episode of venous thrombosis. Duration of anticoagulation in individuals with underlying other thrombosis-provoking conditions like malignancy that increases their risk for recurrent DVT needs to be made based on the underlying condition rather than based on these these thrombophilia conditions. 

Enhancing Healthcare Team Outcomes

Factor V Leiden is not a common disorder, but because there is a potential risk of developing VTE, healthcare professionals should be aware of this disorder. Patients may present with either venous or arterial thrombotic events, both of which are associated with high morbidity and mortality. The condition is best managed by an interprofessional team that includes a hematologist, internist, pharmacist, obstetrician, nurses, and primary care provider. The key reason for such a team is that even when a diagnosis is made, many patients with only a laboratory finding of the defect may not require therapy. Only patients with VTE require treatment. Therefore, all interprofessional team members need to familiarize themselves with the condition and be able to offer patient counsel and watch for signs of VTE. This will require interprofessional care coordination and open communication between team members.

The other difficulty in managing these patients is the duration of therapy. At the moment, data indicate that VTE in factor V Leiden should be managed in the same manner as the normal population, but those with recurrent VTE or thrombosis of vessels in unusual locations may require long-term therapy. The outcomes in most patients with factor V Leiden are good, but the outcomes in pregnant women with the disorder are serious because of morbidity associated with VTE development and VTE-associated complications in pregnancy.[14][15] 

To decrease the morbidity and mortality associated with VTE and post-thrombotic syndrome and complications in pregnant women with VTE, anticoagulation recommendations are put forward by the American Society of Hematology (ASH) and the American College of obstetricians and gynecologists (ACOG).[16] 

Pregnancy being a prothrombotic condition, specific guidelines in managing thrombosis in pregnancy and inherited thrombophilias like factor V Leiden and compound thrombophilias put forward by ASH are summarised in the following table.[16] 

Current or past history of thrombosis Type of thrombophilia  Family history of VTE  Anticoagulation during pregnancy

Anticoagulation postpartum

Choice of anticoagulant

*Do not use DOACs during pregnancy 

*Warfarin is not recommended during pregnancy due to teratogenicity

No Homozygous factor V Leiden Irrespective of family history Prophylactic LMWH throughout pregnancy. Monitoring of anti-Xa levels is not required.

Anticoagulation with LMWH is recommended postpartum.

If not breastfeeding, then DOACs can be used.

LMWH during pregnancy and postpartum, especially in breastfeeding women
No Homozygous FVL+ prothrombin gene mutation Irrespective of family history  Prophylactic LMWH throughout pregnancy.

LMWH in the postpartum period is recommended.

If not breastfeeding, then DOACs can be used

LMWH during pregnancy and postpartum, especially in breastfeeding women.  
No Heterozygous FVL or heterozygous prothrombin gene mutation  Irrespective of family history  No need for prophylactic anticoagulation during pregnancy. No need for prophylactic anticoagulation.  Not needed
No Protein C or S deficiency Yes No need for prophylactic anticoagulation. Postpartum anticoagulation prophylaxis is needed. LMWH postpartum, especially breastfeeding women. 
No Antithrombin III deficiency or homozygous prothrombin gene mutation Yes Prophylactic anticoagulation is needed during pregnancy. 

Postpartum anticoagulation prophylaxis is needed.

If not breastfeeding, then DOACs can be used

LMWH during pregnancy and postpartum,  especially in breastfeeding women 
No Antithrombin III deficiency or homozygous prothrombin gene mutation  No

No prophylaxis needed


 Yes, prophylactic anticoagulation is recommended.  LMWH during  postpartum 
Acute DVT /PE in pregnancy  Irrespective of the thrombophilia  Irrespective of family history

LMW heparin throughout pregnancy and six weeks postpartum

Recommend against thrombolysis  


Routine anti-Xa monitoring is not necessary 

LMWH during pregnancy and postpartum,  especially in breastfeeding women 
Superficial venous thrombosis Irrespective of thrombophilia Irrespective of family history  Suggest LMWH use  Recommend anticoagulation prophylaxis LMWH during pregnancy and postpartum,  especially in breastfeeding women 
Yes-past history of DVT treatment (either unprovoked or associated with hormonal risk factors)  Heterozygous factor V Leiden Irrespective of family history   Suggest LMWH Suggest anticoagulation prophylaxis  LMWH during pregnancy and postpartum, especially in breastfeeding women

DOACs: Direct oral anticoagulants (examples include rivaroxaban, apixaban, dabigatran, or edoxaban); LMWH: Low molecular weight heparin; DVT: Deep venous thrombosis; PE: Pulmonary embolism 



Thorelli E, Kaufman RJ, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood. 1999 Apr 15:93(8):2552-8     [PubMed PMID: 10194434]

Level 3 (low-level) evidence


Dzimiri N, Meyer B. World distribution of factor V Leiden. Lancet (London, England). 1996 Feb 17:347(8999):481-2     [PubMed PMID: 8618525]

Level 3 (low-level) evidence


Stolz E, Kemkes-Matthes B, Pötzsch B, Hahn M, Kraus J, Wirbartz A, Kaps M. Screening for thrombophilic risk factors among 25 German patients with cerebral venous thrombosis. Acta neurologica Scandinavica. 2000 Jul:102(1):31-6     [PubMed PMID: 10893060]


de Moerloose P, Reber G, Perrier A, Perneger T, Bounameaux H. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. British journal of haematology. 2000 Jul:110(1):125-9     [PubMed PMID: 10930988]

Level 2 (mid-level) evidence


Zhang P, Zhang J, Sun G, Gao X, Wang H, Yan W, Xu H, Zu M, Ma H, Wang W, Lu Z. Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis. PloS one. 2014:9(4):e95719. doi: 10.1371/journal.pone.0095719. Epub 2014 Apr 22     [PubMed PMID: 24755609]

Level 1 (high-level) evidence


Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood. 2002 Jul 1:100(1):3-10     [PubMed PMID: 12070000]

Level 2 (mid-level) evidence


Kourlaba G, Relakis J, Kontodimas S, Holm MV, Maniadakis N. A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2016 Jan:132(1):4-10. doi: 10.1016/j.ijgo.2015.06.054. Epub 2015 Oct 9     [PubMed PMID: 26489486]

Level 1 (high-level) evidence


Rosfors S, Norén A, Hjertberg R, Persson L, Lillthors K, Törngren S. A 16-year haemodynamic follow-up of women with pregnancy-related medically treated iliofemoral deep venous thrombosis. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2001 Nov:22(5):448-55     [PubMed PMID: 11735184]

Level 2 (mid-level) evidence


Wik HS, Jacobsen AF, Sandvik L, Sandset PM. Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study. Journal of thrombosis and haemostasis : JTH. 2012 May:10(5):840-7. doi: 10.1111/j.1538-7836.2012.04690.x. Epub     [PubMed PMID: 22452811]

Level 2 (mid-level) evidence


Carroll R, Rebarber A, Booker W, Fox N, Saltzman D, Lam-Rachlin J, Gupta S. Double versus single thrombophilias during pregnancy. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018 Oct:31(19):2590-2593. doi: 10.1080/14767058.2017.1349745. Epub 2017 Jul 16     [PubMed PMID: 28670948]


Perez Botero J, Majerus JA, Strege AK, Johnson RD, Chen D, Pruthi RK. Diagnostic Testing Approaches for Activated Protein C Resistance and Factor V Leiden: A Comparison of Institutional and National Provider Practices. American journal of clinical pathology. 2017 Jun 1:147(6):604-610. doi: 10.1093/ajcp/aqx033. Epub     [PubMed PMID: 28472350]


Amiral J, Vissac AM, Seghatchian J. Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2017 Dec:56(6):906-913. doi: 10.1016/j.transci.2017.11.021. Epub 2017 Nov 14     [PubMed PMID: 29162399]


Tritschler T, Kraaijpoel N, Le Gal G, Wells PS. Venous Thromboembolism: Advances in Diagnosis and Treatment. JAMA. 2018 Oct 16:320(15):1583-1594. doi: 10.1001/jama.2018.14346. Epub     [PubMed PMID: 30326130]

Level 3 (low-level) evidence


Khalafallah AA, Ibraheem AR, Teo QY, Albarzan AM, Parameswaran R, Hooper E, Pavlov T, Dennis AE, Hannan T. Review of Management and Outcomes in Women with Thrombophilia Risk during Pregnancy at a Single Institution. ISRN obstetrics and gynecology. 2014:2014():381826. doi: 10.1155/2014/381826. Epub 2014 Feb 17     [PubMed PMID: 24693443]


Ilonczai P, Oláh Z, Selmeczi A, Kerényi A, Bereczky Z, Póka R, Schlammadinger Á, Boda Z. Management and outcome of pregnancies in women with antithrombin deficiency: a single-center experience and review of literature. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2015 Oct:26(7):798-804. doi: 10.1097/MBC.0000000000000348. Epub     [PubMed PMID: 26226254]


Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James AH, Vazquez SR, Greer IA, Riva JJ, Bhatt M, Schwab N, Barrett D, LaHaye A, Rochwerg B. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood advances. 2018 Nov 27:2(22):3317-3359. doi: 10.1182/bloodadvances.2018024802. Epub     [PubMed PMID: 30482767]

Level 3 (low-level) evidence