Medical Policy: 02.04.46
Original Effective Date: September 2013
Reviewed: May 2016
Revised: May 2016
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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 mutation, and deficiencies in protein S, protein C, and antithrombin. Genetic testing for gene variants associated with thrombophilias is available for factor V Leiden, the prothrombin G20210A mutation, and MTHFR.
Inherited thrombophilias 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 thrombophilias include the following conditions, which are defined by defects in the coagulation cascade:
- Activated protein C resistance (factor V Leiden mutations)
- Prothrombin gene mutation (G20210A)
- Protein C deficiency
- Protein S deficiency
- Prothrombin deficiency
- Hyper-homocysteinemia (MTHFR mutations)
Methylenetetrahydrofolate Reductase (NAD(P)H) (MTHFR) Gene Mutations:
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 mutations in the MTHFR gene have been identified in individuals with homocystinuria. Some mutations cause the enzyme to be inactivated, while others lead to the production of an abnormally small, nonfunctional version of the enzyme. Other gene mutations associated with homocystinuria, include CBS, MTR, MTRR, and MMADHC. In the case of MTHFR mutations, 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 homocyteine have been associated with an increased risk of thromboembolism. Although MTHFR polymorphisms have been associated with increased risk of homocystinuira; genetic testing is not indicated because these variants are not associated with thromboembolism.
MTHFR mutations 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 mutations, including targeted mutation 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 mutations 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 mutations 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.
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.
- 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 who 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.665Cïƒ T, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provider 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:
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 Gynecologist (ACOG)
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.
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.
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.
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 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 mutations 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.
Genetic testing for inherited thrombophilia or recurrent pregnancy loss to include testing for mutations 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 mutation and are considered investigational for the following:
- 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 women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear whether anticoagulation therapy reduces recurrence
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 test 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. Therefore, genetic testing for MTHFR for any indication would be considered investigational.
Clinical utility of testing depends on the balance between the benefit of altering management as a result of knowledge of mutation 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..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
Wellmark's policy is based on:
- 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.
- Society for Maternal-Fetal Medicine Publications Committee. American Board of Internal Medicine (ABIM) Foundation Choosing Wisely Campaign. Available: http://www.choosingwisely.org/doctor-patient-lists/society-for-maternal-fetal-medicine.
- 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. Available online at: http://www.acog.org/~/media/List%20of%20Titles/PBListOfTitles.pdf?dmc=1&ts=20140519T1432 297315.
- 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.
- Up to date
- 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.
Date Reason Action
September 2013 New Policy
July 2014 Annual review Revised policy
June 2015 Annual review Policy revised
May 2016 Annual review Policy revised
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