Medical Policy: 02.04.46 

Original Effective Date: September 2013 

Reviewed: May 2018 

Revised: May 2018 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.



Inherited thrombophilia is a genetic tendency to venous thromboembolism (VTE). Common causes include Factor V Leiden (the most common condition), the prothrombin gene variation, and deficiencies in protein S, protein C, and antithrombin. Genetic testing for gene variants associated with thrombophilia's is available for factor V Leiden, the prothrombin G20210A variation, and MTHFR.


Inherited Thrombophilia

Inherited thrombophilia's are a group of clinical conditions characterized by genetic variant defects associated with a predisposition to thrombosis. However, not all patients with a genetic predisposition to thrombosis will develop VTE. The presence of inherited thrombophilia will presumably interact with other VTE risk factors to determine a patient’s VTE risk.


A number of conditions fall under the classification of inherited thrombophilias. Inherited thrombophilia's include the following conditions, which are defined by defects in the coagulation cascade:

  • Activated protein C resistance (factor V Leiden variation)
  • Prothrombin gene variation (G20210A)
  • Protein C deficiency
  • Protein S deficiency
  • Prothrombin deficiency
  • Hyper-homocysteinemia (MTHFR variation)


Methylenetetrahydrofolate Reductase (NAD(P)H) (MTHFR) Gene Variations

The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase which is important for a chemical reaction involving forms of the B-vitamin folate (i.e., folic acid, vitamin B9). Polymorphisms in the gene have been associated with an increased risk of homocystinuria and neural tube defects, and studied as a possible risk factor for a number of other conditions such as heart disease, stroke, preeclampsia, glaucoma, cleft palate, and certain psychiatric conditions.


At least 40 variations in the MTHFR gene have been identified in individuals with homocystinuria. Some variations cause the enzyme to be inactivated, while others lead to the production of an abnormally small, nonfunctional version of the enzyme. Other gene variations associated with homocystinuria, include CBS, MTR, MTRR, and MMADHC. In the case of MTHFR variations, homocysteine builds up in the bloodstream, and the amount of methionine is reduced. Researchers have not determined how altered levels of homocysteine and methionine lead to the health problems associated with homocystinuria.  Increased levels of homocysteine have been associated with an increased risk of thromboembolism. Although MTHFR polymorphisms have been associated with increased risk of homocystinuria, genetic testing is not indicated because these variants are not associated with thromboembolism.


MTHFR variations have been associated with an increased risk of neural tube defects, such as anencephaly or spinal bifida. The 677C>T variant is the most commonly studied polymorphism. This involves a change in a single deoxyribonucleic acid (DNA) nucleotide in the MTHFR gene, which produces a form of MTHFR that has reduced activity at higher temperatures (i.e., thermolabile). Individuals with the thermolabile form of the enzyme have increased blood levels of homocysteine.


Genotyping for MTHFR variations, including targeted variations analysis, carrier testing, prenatal testing, and full sequence analysis is available in clinical laboratories for MTHFR deficiency (i.e., homocystinuria) and MTHFR thermolabile variant (e.g., cardiovascular disease risk factor, hyperhomocystinemia risk factor, neural tube defect risk factor, preeclampsia risk factor).


Although variations of the MTHFR gene have been associated with increased risk of developing a number of conditions, its role in these conditions has not been established. There is insufficient evidence in the published peer-reviewed scientific literature to determine the clinical utility of genetic testing and its impact on net health outcomes. At this time the role of genetic testing for MTHFR has not been established.


The Genecept™ Assay (Genomind, LLC, Chalfont, PA) is a genetic panel test that includes a range of genetic variations and/or polymorphisms that have been associated with psychiatric disorders and/or response to psychotropic medication. The test consists of a group of individual genes, and the results are reported separately for each gene. The MTHFR is one of the 10 genes included within this assay.


Genetic testing is available for Factor II, Factor V Leiden, Prothrombin gene and MTHFR gene. These tests may include the following within single and panel testing:

  • eSensor® Thrombophilia Risk Test
  • Factor II (Prothrombin) G20210A Kit
  • Factor V Leiden Kit
  • IMPACT Dx™ Factor V Leiden and Factor II Genotyping Test
  • INFINITI™ System Assay for Factor II & Factor V
  • Invader® Factor II, V, and MTHFR tests
  • VeraCode® Genotyping Test for Factor V and Factor II
  • Verigene® Factor F2, F5, and MTHFR Nucleic Acid Test Xpert® Factor II and Factor V Genotyping Assay

Practice Guidelines and Position Statements

Many guidelines and position statements on testing for thrombophilia have been published over the last 2 decades. These guidelines have evolved with time, often do not agree with each other, and do not typically give specific parameters for when to perform genetic testing.


Evaluation of Genomic Applications in Practice and Prevention (EGAPP)

In 2011, the Evaluation of Genomic Applications in Practice and Prevention Working Group published recommendations for genetic testing for FVL mutations and prothrombin mutations.  Recommendations on the clinical utility of genetic testing were:

  • There is no evidence that knowledge of FVL/PT [prothrombin] mutation status in patients with VTE affects anticoagulation treatment to avoid recurrence.
  • There is convincing evidence that anticoagulation beyond 3 months reduces recurrence of VTE, regardless of mutation status.
  • There is no evidence that knowledge of FVL/PT mutation status among asymptomatic family members of patients with VTE leads to anticoagulation aimed at avoiding initial episodes of VTE. 


American College of Medical Genetics (ACMG)


ACMG Practice Guideline: Lack of Evidence for MTHFR Polymorphism Testing

MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analysis have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as part of a routine evaluation for thrombophilia.


ACMG Recommendations:
  • MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss.
  • MTHFR polymorphism genotyping should not be ordered for at risk family members.
  • A clinical geneticist who serves as a consultant for a patient in whom an MTHFR polymorphism(s) is found should ensure that the patient has received a thorough and appropriate evaluation for his or her symptoms.
  • If the patient is homozygous for the "thermolabile" variant c.665C→T, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provide more accurate counseling.
  •  MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation to reduce the risk of neural tube defects as per the general population guidelines.


Society for Maternal-Fetal Medicine

The Choosing Wisely® initiative aims to promote conversations between providers and patients by helping patients choose care that is:

  • Supported by evidence
  • Not duplicative of other tests or procedures already received
  • Free from harm
  • Truly necessary

The Choosing Wisely list created by the Society for Maternal-Fetal Medicine includes Five things physicians and patients should question. The following information is included in this list: Don’t do an inherited thrombophilia evaluation for women with histories of pregnancy loss, intrauterine growth restriction (IUGR), preeclampsia and abruption.


The American College of Obstetricians and Gynecologists (ACOG) (reaffirmed 2017)

The American College of Obstetricians and Gynecologists published an updated practice bulletin addressing management of inherited thrombophilias in pregnancy in September 2011, reaffirmed in 2014.


The thrombotic potential of pregnancy is high, complicating 1 in 1600 births and is the leading cause of maternal morbidity in the United States. The risk is exacerbated by venous stasis in the lower extremities, a hormone-mediated increase in venous capacitance, insulin resistance, and hyperlipidemia. Additionally, inherited thrombophilias are associated with an increased risk for venous thromboembolism (VTE) and also have been linked to adverse outcomes in pregnancy. However, there is limited evidence to guide screening for and management of these conditions in pregnancy.


The aim of this practice bulletin was to review common thrombophilias and their association with maternal VTE risk and adverse pregnancy outcomes, indications for screening to detect these conditions, and management options in pregnancy.


ACOG Recommendations

Specific ACOG recommendations regarding management of inherited thrombophilias in pregnancy include the following:

  • Women who breast-feed may receive postpartum warfarin, low-molecular-weight heparin (LMWH), and unfractionated heparin anticoagulation.
  • For women who have had recurrent fetal loss or placental abruption, inherited thrombophilia testing is not recommended, because it is unclear whether anticoagulation reduces recurrence.
  • In women with previous intrauterine growth retardation or preeclampsia, evidence is insufficient to recommend screening for or treatment of thrombophilias.
  • Screening with fasting homocysteine levels or methylenetetrahydrofolate reductase (MTHFR) mutation analyses is not recommended, because the MTHFR mutation has not been associated with negative pregnancy outcomes.
  • Screening for inherited thrombophilias should include factor V Leiden mutation; prothrombin G20210A mutation; and antithrombin, protein C, and protein S deficiencies.
  • Individualized risk assessment, which may modify management decisions, is recommended for all patients with inherited thrombophilias.


International Society on Thrombosis and Haemostasis

The Prevention of Venous Thromboembolism in Pediatric Cancer


Guidance statement:

  1. We recommend that a comprehensive risk assessment be performed on each pediatric cancer patient at the initiation of cancer therapy.
  2. We recommend against routine primary thrombopro-phylaxis in pediatric cancer patients without a historyof prior thrombosis.
  3. We recommend thromboprophylaxis in pediatric cancer patients with prior thrombosis who are continuing to receive intensive therapy, so long as there are no contraindications to anticoagulation.
  4. We suggest that thromboprophylaxis should be considered, on a case-by-case basis, for pediatric cancer patients with no history of VTE, but with significant combinatorial risk  factors  (e.g. CVC, asparaginase therapy, obesity, adolescence, hormonal contraceptives or hospitalization for surgery).


CHEST Guidelines on Antithrombotic Therapy for VTE Disease (2016) do not mention genetic testing for venous thrombosis.


Clinical Utility

Clinical utility of genetic testing depends on the ability of testing results to change management that results in improved outcomes. Clinical utility of genetic testing for thrombophilia is considered in the context of overall VTE risk and risk/benefit ratio of treatment, primarily with anticoagulants. The following factors are part of the decision-making process on whether to test:

  • Overall low incidence of thromboembolism in the general population
  • Modest increased risk associated with most forms of inherited thrombophilia, meaning that the absolute risk of thrombosis in patients with inherited thrombophilia is still relatively low.
  • Potential risk of prophylactic treatment, especially bleeding risk with anticoagulation. This risk may outweigh benefit in patients with a relatively low absolute risk of thrombosis.

Population-based screening for inherited thrombophilia is not recommended because of three salient factors:


  • The low frequency of the symptomatic condition in the general population

  • The low penetrance of the symptomatic condition among carriers of the most common thrombophilic conditions (eg, factor V Leiden and prothrombin G20210A variations),

  • The lack of a safe, cost-effective, long-term method of prophylaxis if an abnormality is found.


    Geno typical women with a past history of idiopathic (unprovoked) or recurrent VTE are at relatively high risk of recurrent thrombosis and should receive thromboprophylaxis antepartum regardless of thrombophilia status. For geno typical women with a prior VTE associated with estrogen-progestin contraceptive use or pregnancy, there is a recommendation for  prophylactic anticoagulation whether or not a thrombophilic defect is identified. Therefore, the knowledge of defect status does not affect treatment.


    Given the low absolute risk of VTE, and the defined risks of anticoagulation, it is not possible to define a clinical situation in which the benefit of testing clearly outweighs the risk. Because of the lack of documented clinical utility, evidence for genetic testing for inherited thrombophilia is considered insufficient to demonstrate improvement in net health outcome. There is insufficient evidence in the published peer-reviewed scientific literature to determine how testing for variations in the Factor V Leiden gene, the Prothrombin gene, or the MTHFR genes guides decisions in the clinical setting related to disease treatment, management or prevention.


    Studies that show how test results impact treatment decisions and how these modified treatments improve net health outcome compared with no testing are required.  Surveys of physicians indicate that a substantial number order thrombophilia testing with the intent of influencing management, but specific management changes and the impact of those management changes on outcomes are uncertain. According to existing evidence and recent evidence-based guidelines, the presence of inherited thrombophilia is not an important factor in determining the optimal duration of anticoagulation in patients with VTE.


    Published guidelines do not address whether the presence (or absence) of an (inherited thrombophilia)IT should influence the duration of therapy for a child with VTE. The decision of how long to continue anticoagulation therapy for VTE in pediatric patients is based largely on the age of the child (shorter treatment courses may be used in neonates compared with older infants and children) and whether the VTE is provoked (ie, associated with a risk factor such as CVC, estrogen, infection, trauma, or immobilization) or unprovoked (unprovoked VTE is generally treated for a longer duration compared with provoked).


    Prior Approval:


    Not applicable



    Genetic testing for inherited thrombophilia or recurrent pregnancy loss to include testing for variations in the MTHFR gene is considered investigational.


    Genetic testing for MTHFR for diagnosis or management of all other indications, including but not limited to, depression, coronary artery disease, cancer, congenital heart defects, Alzheimer’s, dementia, hepatitis, stroke, infertility, Parkinson’s, migraines, peripheral neuropathy, diabetic retinopathy, autism spectrum disorder, nitrous oxide use, schizophrenia and vascular disease is considered investigational.


    Genetic testing for gene variants associated with thrombophilias is available for factor V Leiden and the prothrombin G20210A variation and are considered investigational for the following, but not limited to:

    • Assessment of the risk for thrombosis in asymptomatic patients (screening for inherited thrombophilia)
    • Evaluation of a patient with established thrombosis, for consideration of change in anticoagulant management based on results
    • Evaluation of patients in other situations that are considered high risk for thrombosis, e.g. pregnancy, planned major surgery, or oral contraceptive use
    • Testing for inherited thrombophilias in geno typical women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear whether anticoagulation therapy reduces recurrence


    Testing for Factor V (F5) HR2 allele DNA variation analysis is considered investigational for all indications. The clinical validity is unproven at this time.


    Genetic testing for Hemophilia C (Factor XI, F11) is considered investigational.  The clinical validity is unproven at this time.


    There are no clinical situations in which testing is either mandatory or specifically recommended in guidelines due to generally insufficient clinical utility data.  There are no recommended changes in management that are linked to specific test results. Management changes that might be made include selection of specific medications according to test results, discontinuation of medications, changes in dosing of medications among other ill-defined management changes. However, these management changes are not well-defined and may vary according to the judgment of the treating clinician. Since management changes are ill-defined, it is not possible to determine whether management changes associated with the tests lead to improvements in health outcomes. In conclusion, there is insufficient evidence in the published peer reviewed scientific literature regarding the clinical utility and its impacts on health outcomes.


    Clinical utility of testing depends on the balance between the benefit of altering management as a result of knowledge of variation status versus the risk of bleeding with intensification of anticoagulation. This risk-benefit is unknown, as previously discussed. Absolute risk of VTE remains low even in patients with inherited thrombophilia, and potential risks of prophylactic treatment with anticoagulants may outweigh potential benefits. Testing in select populations of patients with VTE leads to the increased identification of hypercoagulable states, it infrequently alters the duration of anticoagulation or prevents VTE-related death. Therefore, genetic testing for inherited thrombophilias for any individual, regardless of family history, would be considered investigational.


    Information regarding the use of MTHFR, Factor V, and prothrombin testing can also be found in the following policy:  02.04.04 Cardiovascular Disease Risk Tests


    Procedure Codes and Billing Guidelines:

    To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

    • 81291  MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants
    • 81240  F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant
    • 81241  F5 (coagulation factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant


    Selected References:

    • American College of Medical Genetics Practice Guidelines: Lack of Evidence for MTHFR Polymorphism Testing. Scott E. Hickey, M.D., FACMG, Cynthia J. Curry, M.D., FACMG and Helga V. Toriello, PhD, FACMG, Genetics in Medicine 2013:15(2):153-156
    • American College of Obstetricians and Gynecologist (ACOG) Inherited Thrombophilias in Pregnancy. September 11, 2011 ACOG practice bulletin; no 124
    • National Institute of Health (NIH). Genetics Home Reference. MTHFR. Reviewed July 2011.
    • American Heart Association Journals 2005; 111: e289-e293: Homocysteine and MTHFR Mutations, Relation to Thrombosis and Coronary Artery Disease, Elizabeth A. Varga, MS; Amy C. Sturm MS; Caron P. Misita, ParmD; Stephan Moll M.D.
    • Nagele, P., Brown F., Francis A., Scott MG., et al. Influence of nitrous oxide anesthesia, B-Vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial. Anesthesiology. 2013 Jul;119(1):19-28. doi: 10.1097/ALN.0b013e31829761e3.
    • Society for Maternal-Fetal Medicine Publications Committee American Board of Internal Medicine (ABIM) Foundation Choosing Wisely Campaign.
    • Guyatt GH, Akl EA, Crowther M et al. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(2_suppl):7S-47S.
    • Li P, Qin C. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and susceptibility to ischemic stroke: A meta-analysis. Gene 2014; 535(2):359-64.
    • Supanc V, Sonicki Z, Vukasovic I et al. The role of classic risk factors and prothrombotic factor gene mutations in ischemic stroke risk development in young and middle-aged individuals. J Stroke Cerebrovasc Dis 2014; 23(3):e171-6.
    • ACOG. American College of Obstetrics and Gynecology. Practice bulletin no. 138: inherited thrombophilias in pregnancy, September 2013.
    • Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6.
    • Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149:209.
    • Lijfering WM, Brouwer JL, Veeger NJ, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113:5314.
    • Holzhauer S, Goldenberg NA, Junker R, et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood 2012; 120:1510.
    • Wu O, Robertson L, Langhorne P, et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94:17.
    • Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996; 313:1127..
    • Middeldorp S, Henkens CM, Koopman MM, van Pampus EC, Hamulyák K, van der Meer J, Prins MH, Büller HR The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med. 1998;128(1):15.
    • Bates SM, Greer IA, Middeldrop S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy. In antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e691S-736S.
    • Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (2021G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 2011;13(1)67-76.
    • Rodger MA, Walker MC, Smith GN, et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost 2014 Jan 21.
    • Guyatt GH, Akl EA, Crowther M, et al. American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence­Based Clinical Practice Guidelines. Chest. 2012;141:7S–47S.
    • ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122:706-17. (reaffirmed 2017)
    • Gupta, A., Sarode, R., Nagella, S. Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Intern Med 2017;Jun 5:[Epub ahead of print]. 
    • Prosciak MP, Stawicki SP. Hypercoagulable states: A concise review. Int J Acad Med 2017;3, Suppl S1:82-95. 
    • Bauer, K., Lip, G. Overview of the causes of venous thrombosis. Apr 2018.  
    • Tullius BP, Athale U, van Ommen CH, Chan AKC, Palumbo JS, Balagtas JMS, for the Subcommittee on Hemostasis and Malignancy and the Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis. The identification of at-risk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16: 175–80.
    • Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Intern Med 2017;Jun 5:[Epub ahead of print].
    • Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. Feb 2016;149(2):315-352. PMID 26867832


    Policy History:

    • May 2018 - Annual Review, Policy Revised
    • May 2017 - Annual Review, Policy Revised
    • May 2016 - Annual Review, Policy Revised
    • June 2015 - Annual Review, Policy Revised
    • July 2014 - Annual Review, Policy Revised
    • September 2013 - New Policy 

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