Coverage Policy Manual
Policy #: 2004044
Category: Laboratory
Initiated: July 2004
Last Review: August 2023
  Genetic Test: Factor V Leiden
Description:
Factor V Leiden thrombophilia is an inherited disorder of blood clotting caused by mutations in the F5 gene.  The protein made by this gene is involved in a series of chemical reactions that hold blood clots together.  A molecule called activated protein C (APC) prevents blood clots from growing too large by inactivating factor V but it does not function properly in people with the factor V Leiden mutation.  The mutant factor 5 Leiden is inactivated at an approximately tenfold slower rate and persists longer in the circulation resulting in a mild hypercoagulable state.
 
Heterozygosity for factor V Leiden occurs in 3%-8% of the general US and European populations; the mutation is rare in Asian, African, and indigenous Australian populations.  Heterozygous carriers have a 2- to 8-fold increase in relative risk of thrombosis compared to individuals with no mutations, but only a 4 to 10% lifetime probability of thrombosis.  Homozygous carriers or carriers of multiple defects are rare, but have a markedly increased risk of thrombosis.  Mutation carriers, in combination with other risk factors for thrombosis (e.g. pregnancy, oral contraceptive use, hormone replacement therapy, surgery, or trauma) have a significant elevation in risk beyond the risk associated with the mutation alone.
 
Prior to the discovery of the factor V Leiden mutation, the defect was identified by a functional activated protein C assay (APC); this assay remains an acceptable first step in the testing process.  
 
Coding Effective 2015
A Specific CPT code for this testing became available in 2012:
 
81241: F5 (coagulation Factor V)(e.g., hereditary hypercoagulability) gene analysis, Leiden variant
 
Coding Prior to 2015
A Specific CPT code for this testing became available in 2012:
 
81241: F5 (coagulation Factor V)(e.g., hereditary hypercoagulability) gene analysis, Leiden variant
 
There is a specific HCPCS code for this testing:  S3843-DNA analysis of the F5 gene for susceptibility to factor V Leiden thrombophilia.
 
Prior to 2012, Genetic modifier -3A would have been used with a series of molecular diagnostic codes to identify testing for the F5 gene.
 
 
Policy/
Coverage:
Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
Genetic testing for factor V Leiden (R506Q mutation) meets primary coverage criteria for effectiveness and is covered in the following circumstances:
    • A patient with venous thrombosis, age < 50 years, except when active malignancy is present
    • A patient with venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins)
    • A patient with recurrent venous thrombosis
    • A patient with venous thrombosis and a strong family history of thrombotic disease
    • A pregnant woman with venous thrombosis or a woman with venous thrombosis who is taking oral contraceptives
    • A female smoker under the age of 50 with a Myocardial infarction
    • Genetic testing for factor V Leiden (R506Q mutation only) may meet primary coverage criteria for effectiveness and be covered when an activated protein C (APC) level is low for:
      • Venous thrombosis, age > 50, except when active malignancy is present
      • Women with recurrent pregnancy loss or unexplained  severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth.  Knowledge of factor V Leiden status could influence the management of future pregnancies.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for factor V Leiden (R506Q mutation) for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria genetic testing for factor V Leiden (R506Q mutation) for all other indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Rationale:
Group contracts furnished or renewed on or after July 1, 2004 or individual contracts furnished on or after July 1, 2004 have the following coverage for genetic testing:
    • Services for genetic testing to determine the likelihood of developing a disease or condition, the likelihood of a disease or the presence of a disease in a relative, or the likelihood of passing an inheritable disease or congenital abnormality to an offspring, are not covered.
    • Services for pre-implantation genetic diagnosis or treatment are not covered.
    • However, subject to all terms, conditions, exclusions and limitations of the Plan set forth in this Benefit Certificate, genetic testing of the products of an amniocentesis, to determine the presence of a disease or congenital anomaly in the fetus, or genetic testing of a Covered Person’s tissue to determine if the Person has a specific disease (not to determine if the person is a carrier of a genetic  abnormality), is covered.  See Subsection dealing with Pre-Natal Tests.]
 
The American College of Medical Genetics published a consensus paper on Factor V Leiden Mutation Testing in March/April 2001.  The document was reaffirmed in 2006.  The following lists some of the information from that paper:
“There is growing consensus that testing should be performed in at least the following circumstances:
    • Age < 50, any venous thrombosis
    • Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins)
    • Recurrent venous thrombosis
    • Venous thrombosis and a strong family history of thrombotic disease
    • Venous thrombosis in pregnant women or women taking oral contraceptives
    • Relatives of individuals with venous thrombosis under age 50
    • Myocardial infarction in female smokers under age 50
 
“Testing may also be considered in the following situations:
    • Venous thrombosis, age >50, except when active malignancy is present
    • Relatives of individuals known to have factor V Leiden.  Knowledge that they have factor V Leiden may influence management of pregnancy and may be a factor in decision-making regarding oral contraceptive use.
    • Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth.  Knowledge of factor V Leiden carrier status may influence management of future pregnancies.
 
“Routine testing is not recommended for patients with a personal or family history of arterial thrombotic disorders (e.g., acute coronary syndromes or stroke) except for the special situation of myocardial infarction in young female smokers.  Testing may be worthwhile for young patients (<50 years of age) who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease.
 
“Routine screening for factor V Leiden in asymptomatic women contemplating or using oral contraceptives is not recommended, except for those with a personal history of thromboembolism or other medical risk factors.”
 
Whether or not testing for Factor V Leiden and prothrombin G20210A improves patient outcomes is controversial.  
    • Screening the general, asymptomatic population is not recommended.
    • Screening all asymptomatic women prior to prescribing oral contraceptives or hormone replacement therapy is not recommended.
    • Screening all pregnant women and administering prophylactic anticoagulation therapy to carriers is not recommended.
    • Testing for hereditary thrombophilia in all patients with a first venous thromboembolism is controversial.  There is little evidence to support changes in management and improved outcomes for patients found to be mutation positive.
    • However, when additional risk factors are present or are being considered in patients suspected to have hereditary thrombophilia, test results for hereditary risk factors may influence choices or therapy.
    • “Neither prenatal testing nor routine newborn screening is recommended."
 
In a 2005 survey of ACOG Fellows and Junior Fellows  Cleary-Goldman et al found 92% tested patients with recurrent miscarriages for antiphospholipid antibodies.  "Despite no clear evidence, 80% also test these patients for inherited thrombophilias."
 
2011 Update
The EGAPP Working Group published recommendations on the routine testing of Factor V Leiden (R506Q) (FVL) and prothrombin (20210G>A) (PT) mutations in adults with a history of idiopathic venous thromboembolism.  The EGAPP working group was organized to conduct an evidence-based review to make a decision on the clinical utility of testing for FVL mutations alone or in combination with PT mutation testing.  The group recommended against routine testing of FVL and PT in adults with idiopathic venous thromboembolism and the asymptomatic relatives of patients with VTE and a Factor V Leiden or PT mutation.  
 
The group found that the evidence suggests that prophylaxis to avoid a recurrence of VTE yields the same results in patients with and without one or more of these mutations.  In asymptomatic family members, the benefits of prophylaxis are unlikely to outweigh the potential harms.  The group reports that there have been no prophylaxis trials in asymptomatic family members and there is no direct evidence that prophylaxis is of any benefit to family members of patients with VTE and an FVT and/or PT mutation.
 
2012 Update
A search of the MEDLINE database through July 2012 did not reveal any new literature that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2018, the American College of Medical Genetics and Genomics (ACMG) published updated technical standards for genetic testing for variants associated with VTE, with a focus on factor V Leiden and factor II (Zhang, 2018). The standards do not make recommendations on the indications for testing, and the authors note that testing indications from different professional organizations vary, referring to a review of professional society guidelines published by de Stefano et al (De Stefano, 2013).
 
In 2019, Stevens et al. published a guidance document initiated by the Anticoagulation Forum (Stevens, 2016). The guidance was intended to inform clinical decisions regarding duration of anticoagulation following VTE and primary prevention of VTE in relatives of affected patients. Statements were based on existing guidelines and consensus expert opinion when guidelines were lacking. The authors concluded that, "Thrombophilia testing is performed far more frequently than can be justified based on available evidence; the majority of such testing is not of benefit to the patient and may be harmful."
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A systematic review by Liu et al evaluated the association between hereditary thrombophilias, including FVL and prothrombin G20210A, and recurrent pregnancy loss (Liu, 2021). Observational studies were included if they compared at least 2 groups of patients - 1 with hereditary thrombophilia and 1 without hereditary thrombophilia. There were 89 studies included in the analysis, with 81 evaluating the risk of FVL and 64 evaluating the risk of prothrombin G20210A on recurrent pregnancy loss. Pooled analysis of FVL demonstrated an increased risk for recurrent pregnancy loss with the variant (OR=2.44; 95% CI, 1.96 to 3.03). Pooled analysis for prothrombin G20210A also demonstrated an increased risk for recurrent pregnancy loss with the variant (OR=2.08; 95% CI, 1.61 to 2.68). Both analyses were limited by high heterogeneity across the included studies.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Since 2016, the American College of Chest Physicians guidelines and expert panel report on antithrombotic therapy for venous thromboembolism (VTE) disease no longer includes recommendations for pregnant women with known factor V Leiden or prothrombin G20210A variants, which had been included in the 2012 edition (Kearon, 2016; Guyatt, 2012; Stevens, 2021). Also, there are no guidelines on genetic testing for thrombophilia. The 2008 edition had indicated that the presence of a hereditary thrombophilia was not a major factor to guide duration of anticoagulation for VTE (Hirsh, 2008).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
81241F5 (coagulation factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant
References: Cleary-Goldman J, Bettes B, et al.(2007) Thombophilia and the obstetric patient. Obstet Gynecol, 2007; 110:669-74.

De Stefano V, Rossi E.(2013) Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost. Oct 2013; 110(4): 697-705. PMID 23846575

EGAPP Working Group.(2011) Recommendations from the EGAPP Working Group: Routine testing for FVL(R506Q) and PT (20210GA) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med. 2011 Jan;13(1):67-76.

Gao M, Feng N, Zhang M, et al.(2020) Meta-analysis of the relationship between methylenetetrahydrofolate reductase C677T and A1298C polymorphism and venous thromboembolism in the Caucasian and Asian. Biosci Rep. Jul 31 2020; 40(7). PMID 32614041

Grody WW, Griffin JH, et al.(2006) American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Accessed 10/5/07, www.acmg.net.

Grody WW, Griffin JH, Taylor AK, et al. (ACMG Factor V Leiden Working Group).(2001) American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Genetics in Medicine 2001; 3:139-148.

Guyatt GH, Akl EA, Crowther M, et al.(2012) Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012; 141(2 Suppl): 7S-47S. PMID 22315257

Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology.(2001) Guideline. Investigation and management of heritable thrombophilia. Br J Haematol, 2001; 114:512-28.

Hirsh J, Guyatt G, Albers GW, et al.(2008) Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008; 133(6 Suppl): 110S-112S. PMID 18574260

Kearon C, Akl EA, Ornelas J, et al.(2016) Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. Feb 2016; 149(2): 315-352. PMID 26867832

Kujovich JL.(2007) Factor V Leiden thrombophilia. GeneReviews, Feb 2007. www,genetests.org.

Merriman L, Greaves M.(2006) Testing for thrombophilia: an evidence-based approach. Postgrad Med J, 2006; 82:699-704.

Pruller F, Weiss EC, Raggam RB, et al.(2014) protein C resistance assay and factor V Leiden. N Engl J Med. Aug 14 2014;371(7):685-686. PMID 25119624

Stevens SM, Woller SC, Bauer KA, et al.(2016) Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis. Jan 2016; 41(1): 154-64. PMID 26780744

Stevens SM, Woller SC, Kreuziger LB, et al.(2021) Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. Dec 2021; 160(6): e545-e608. PMID 34352278

Zhang S, Taylor AK, Huang X, et al.(2018) Venous thromboembolism laboratory testing (factor V Leiden and factor II c.*97G A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. Dec 2018; 20(12): 1489-1498. PMID 30297698
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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