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 Thrombophilia
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:
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:
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:
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 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.
ACOG Recommendations
Specific ACOG recommendations regarding management of inherited thrombophilias in pregnancy include the following:
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:
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.
Not applicable
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:
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
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