Medical Policy: 02.04.46
Original Effective Date: September 2013
Reviewed: May 2020
Revised: May 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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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 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'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:
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.
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. While standard of care for work up of VTE or DVT is to perform protein activity and antigen studies, Factor V and Prothrombin studies are easiest to perform as molecular genotyping given that these conditions are almost always caused by a common variant. There have been conflicting recommendations as to how to approach genetic testing for thrombophilias. ACMG and ACOG have recommended testing for F2 and F5 in certain scenarios, while the Evaluation of Genomic Applications and Prevention Working Group (EGAPP) found insufficient evidence to perform this testing for any indication. The presence of an inherited thrombophilia variant itself does not always require prophylactic treatment with anticoagulants, and other risk factors should be considered when assessing a patient’s individual risk of VTE and the need for anticoagulation therapy.
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:
Evaluation of Genomic Applications and Prevention Working Group (EGAPP) found insufficient evidence to perform this testing for any indication. The presence of an inherited thrombophilia variant itself does not always require prophylactic treatment with anticoagulants, and other risk factors should be considered when assessing a patient’s individual risk of VTE and the need for anticoagulation therapy (2019).
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 has released guidelines for laboratory testing of venous thromboembolism (VTE). This 2018 edition superseded the 2005 edition. The guidelines are as follows:
Testing for factor V Leiden and factor II c.*97G>A (this mutation is also known as G20210A) is recommended in the following circumstance:
Testing may be considered in the following circumstances:
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 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:
Do not perform thrombophilia testing following an episode of provoked VTE.
Do not perform thrombophilia testing in patients following an episode of unprovoked VTE.
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia.
If a woman contemplating estrogen use has a first-degree relative with VTE and a known hereditary thrombophilia test for that thrombophilia only if the result would change the decision to use estrogen.
Do not perform thrombophilia testing at the time of VTE diagnosis or during the initial 3-month course of anticoagulant therapy. When testing for thrombophilias following VTE, use either a 2-stage testing approach or perform testing after a minimum of 3 months of anticoagulant therapy has been completed, and anticoagulants have been held.
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia who are contemplating pregnancy. If a woman contemplating pregnancy has a first-degree relative with VTE and a known hereditary thrombophilia… test for that thrombophilia if the result would change VTE prophylaxis decisions.
CHEST Guidelines on Antithrombotic Therapy for VTE Disease (2016) do not mention genetic testing for venous thrombosis.
The clinical validity of genetic testing has been demonstrated by the presence of a factor V Leiden variant or a prothrombin gene variant, and an association with an increased risk for subsequent VTE across various populations studied. However, the magnitude of the association is relatively modest, with odds ratios most commonly between 1 and 2, except for family members of individuals with inherited thrombophilia, for whom odds ratios are somewhat higher.
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:
Population-based screening for inherited thrombophilia is not recommended because of three salient factors:
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).
| Test | Manufacturer |
|---|---|
| IMPACT Dx™ Factor V Leiden and Factor II Genotyping Test | Agena Biosciencea |
| Invader® Factor II, V, and MTHFR (677, 1298) tests | Hologic |
| VeraCode® Genotyping Test for Factor V and Factor II | Illumina |
| eSensor® Thrombophilia Risk Test, FII-FV, FII, FV and MTHFR (677, 1298) Genotyping Tests | GenMark Dxb |
| INFINITI™ System Assay for Factor II & Factor V | AutoGenomics |
| Xpert® Factor II and Factor V Genotyping Assay | Cepheid |
| Verigene® Factor F2, F5, and MTHFR Nucleic Acid Test | Nanosphere |
| Factor V Leiden Kit | Roche Diagnostics |
| Factor II (Prothrombin) G20210A Kit | Roche Diagnostics |
Not applicable
See policy 02.04.04 Cardiovascular Disease Risk Tests for additional information regarding the use of MTHFR, Factor V, and prothrombin
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:
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.
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. Recent study results indicate that there is a similar rate of VTE recurrence for carriers of FVL or PGM and non-carriers. Additionally, there is evidence that this testing rarely leads to treatment changes or changes in net health outcomes. Therefore, genetic testing for inherited thrombophilias for any individual, regardless of family history, would be considered investigational.
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