Factor V Leiden Mutation

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Continuing Education Activity

Factor V Leiden (FVL) is a point mutation of factor V resulting in an elimination of cleavage site in factor V and factor Va. This genetic defect leads to an increased risk of thrombosis especially in homozygous or pseudo-homozygous FVL 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 of the people who carry the mutation will never have VTE. This activity reviews the pathophysiology and implications of factor V Leiden and highlights the role of the interprofessional team in its management.


  • Describe the pathophysiology of Factor V Leiden.
  • Review the clinical manifestations of factor V Leiden. Outlines the importance of combined thrombophilia conditions
  • Summarize the treatment of factor V Leiden. Reviews the prophylaxis for venous thromboembolism during pregnancy and during the postpartum period for women with FVL with or without a family history of thromboembolism.
  • Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by factor V Leiden Leiden.


Factor V Leiden (FVL) is a point mutation of factor V resulting in an elimination of cleavage site in factor V and factor Va. This genetic defect leads to an increased risk of thrombosis especially in homozygous or pseudo-homozygous FVL 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 of the people who carry the mutation will never have VTE.


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 who has the mutation will develop the disease. 

VFL, 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 APC in Factor V and Va.[1]

FVL 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 for the FVL mutation is the most common inherited thrombophilia in the unselected Caucasian population (prevalence, approximately 1% to 5%) and is considered the most common inherited thrombophilia in individuals with venous thromboembolism (prevalence approximately 10% to 20%). [2] Heterozygosity of this gene increases the lifetime risk of thrombosis 7-fold, while homozygosity (which is rare) increases the risk 20 fold.

Despite the increase in the risk of VTE, there is no clinical evidence that heterozygosity to FVL increases the overall mortality.


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

Venous Thromboembolism

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

Arterial Thromboembolism

  • Association between FVL 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 FVL. It has been observed that the FVL mutation is associated with an increased risk of stroke especially in women, smokers, and younger individuals.[5]

Pregnancy and postpartum thromboembolism risk

  • Thromboembolism affects 1.2 of every 1000 deliveries [6]. Increased morbidity and mortality are reported with pregnancy-associated VTE for women [7][8]. However, inherited thrombophilia like FVL based on clinical evidence as of now are neither considered risk factors for recurrent pregnancy losses nor are implicated to affect obstetrical outcomes [9]
  • Women with FVL 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 by ASH ( American Society of Hematology ) guidelines as it is expensive with no clinically meaningful benefit 

Testing for FVL is indicated for individuals with venous thromboembolism, especially if:

  • VTE occurring at a young age generally speaking less than 50 yrs of age
  • Atypical sites of clotting like visceral veins thromboses like an ovarian 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.

FVL can be diagnosed by mutation analysis (DNA testing) or a functional coagulation test for APC resistance.

  • Genetic testing is indicated for those with a family history of FVL. 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.[10]
  • Mutation testing: Polymerase chain reaction methods can detect FVL 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 FVL mutation resulting in a different banding pattern on a DNA gel.[11]
  • 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 inhibitor, as well as in presence of a lupus anticoagulant.

Treatment / Management

Management of venous thromboembolism in people with FVL mutation is the same as that of the general population, and FVL 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 those who present with a submissive/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 FVL 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.[12]

Individuals with FVL heterozygous 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 (PGM)
  • Protein S deficiency 
  • Protein C deficiency
  • Antithrombin (AT) deficiency


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


A proportion of the population with Factor V Leiden will suffer 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 FVL increases overall mortality.

Pearls and Other Issues

Pertinent to FVL its important to understand the relative risk of VTE risk compared to other thrombophilia conditions that help to guide management decisions.  This risk is given in the below table format for easy understanding.

Thrombophilia Condition The relative increase in the risk of thrombosis
FVL heterozygous 4.9 fold (3-8 fold) 
FVL Homozygous 16 fold
FVL with other thrombophilia conditions like 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 (PGM) heterozygous 3.8 fold

So a patient having low-risk thrombophilia conditions like FVL heterozygous, PGMheterozygous, Protein C, Protein S deficiency does not require lifetime anticoagulation.  Thus patients with low-risk thrombophilia conditions management are no different than the management guidelines of the general population.  Per ASH guidelines 3-6 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 low-risk 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 workers 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, nurse practitioner, pharmacist, obstetrician, 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. The other difficulty in managing these patients is the duration of therapy. At the moment, data indicate that VTE in factor Leiden mutation 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 deficiency 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 [13][14]. To decrease the morbidity and mortality associated with VTE and post-thrombotic syndrome and complications to 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) [15] 

Pregnancy being a prothrombotic condition, specific guidelines in the management of thrombosis in pregnancy and inherited thrombophilias like FVL and compound thrombophilias put forward by ASH that is summarised as below [15] 

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 FVL Irrespective of family history Prophylactic LMWH throughout pregnancy. Monitoring of Anti X is not required.

 Anticoagulation with LMWH is recommended postpartum.

 If not breastfeeding then DOACS can be used

LMWH during pregnancy and postpartum especially breastfeeding women 
No Homozygous FVL+ PGM  Irrespective of family history  Prophylactic LMWH throughout pregnancy 

LMWH in the postpartum period recommended

 If not breastfeeding then DOACS can be used

LMWH during pregnancy and postpartum especially 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 needed  LMWH during  postpartum especially breastfeeding women 
No Antithrombin III deficiency or Homozygous prothrombin gene mutation Yes Prophylactic anticoagulation is needed during pregnancy 

 Postpartum anticoagulation prophylaxis 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 recommended  LMWH during  postpartum 
 Acute DVT /PE in pregnancy  Irrespective of the thrombophilia  Irrespective of family history

LMW heparin throughout pregnancy and 6 weeks postpartum

recommend against thrombolysis  


routine anti X monitoring not necessary 

 LMWH during pregnancy and postpartum especially breastfeeding women 
 Superficial venous thrombosis Irrespective of thrombophilia Irrespective of family history  Suggest LMW Heparin use  Recommends anticoagulation prophylaxis  LMWH during pregnancy and postpartum especially breastfeeding women 
Yes-past history of DVT treated  either unprovoked or associated with hormonal risk factor  Heterozygous FVL Irrespective of family history   Suggest LMWH  Suggest anticoagulation prophylaxis   LMWH during pregnancy and postpartum if breastfeeding (LMWH preferred) 

DOACs: Direct oral anticoagulants examples of which are Rivaroxaban, Apixaban, etc; LMWH: Low Molecular Weight Heparin; DVT: Deep venous thrombosis; PE: Pulmonary Embolism 

Article Details

Article Author

Sara A. Albagoush

Article Author

Supriya Koya

Article Author

Rebanta K. Chakraborty

Article Editor:

Amy E. Schmidt


4/22/2022 12:48:27 PM



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