Genetic Testing for Inherited Thrombophilia

• Notice
• Benefit Application
• Description
• Prior Approval
• Policy
• Procedure Codes
• Selected References
• Policy History

 

Medical Policy: 02.04.46 

Original Effective Date: September 2013 

Reviewed: May 2021 

Revised: May 2021 

 

Notice:

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.

 

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.

 

Description:

Thrombophilia is a disorder of blood coagulation that increases the risk for blood clots (thrombosis) in veins or arteries. Thrombophilia can be acquired or inherited. The most common acquired thrombophilias occur as a result of injury, surgery or a medical condition. The most common hereditary thrombophilias are Factor V Leiden (FVL), due to a mutation in the F5 gene and prothrombin G20210A, as a result of a mutation in the F2 gene.

 

Factor V Leiden (FVL) variant is the most common heritable prothrombotic risk factor in the United States, with the Leiden variant accounting for 90% to 95% of activated Protein C resistance. Both heterozygotes and homozygotes are at increased risk of occurrence or recurrence of venous thromboembolism (VTE). However, clinical expression of the FVL variant is variable and many individuals with the FVL allele never develop thrombosis. The risk of VTE among pregnant women who are heterozygous for FVL without a personal history of VTE or an affected first-degree relative with a thrombotic episode before age 50 years is less than 0.3%, while this risk increases to at least 10% among pregnant women with a personal or family history of venous thromboembolism. 

 

Prothrombin G20210A is known to be associated with coagulation factor 2 (F2) prothrombin-related thrombophilia. Individuals heterozygous for this variant have an approximately two-to four-fold increased risk of VTE as compared to individuals without the variant. Individuals who are homozygous for the variant may have a more severe thrombophilia and/or an increased risk for thrombosis; however, the number of individuals who are homozygous for the variant is small and it is difficult to determine the risk of VTE in this population. 

 

There is general consensus by a number of professional societies/organizations that testing for Factor V Leiden (FVL) and Prothrombin G20210A (F2) is appropriate in selected individuals as an option to inform treatment. The decision to test should be based on clinical utility, that is, the likelihood that test results will impact clinical management (ACOG, ACMG, ACCP). Testing allows for prophylactic and/or ongoing clinical management including thromboprophylaxis and/or modification of risk factors. Persons for whom there is professional consensus regarding clinical utility for testing are:

 

• Pregnant woman who has a personal history of venous thromboembolism (VTE)
• In an individual with an unprovoked VTE (e.g., not associated with fracture, surgery, prolonged immobilization, cancer) when test results will impact long term medication management and at least one of the following:
• Concern for homozygous F2 or F5 or compound heterozygous F2/F5
• Annual risk of recurrent VTE is estimated to be between 5% and 10%
• Individual who has a first-degree relative (i.e., parent, full-sibling, child) with Factor V Leiden thrombophilia or F2 G2021A (prothrombin) thrombophilia and ONE of the following:
• Surgery is planned
• pregnant
• Female who is considering estrogen contraception or hormone replacement therapy if results would influence decision to use estrogen 

 

Potential consequences of identifying a thrombophilic defect in a patient with venous thromboembolism (VTE) include prolonging the anticoagulant therapy beyond three-six months or prescribing a more aggressive thromboprophylaxis in at-risk situations such as surgery, pregnancy or prolonged immobility. 

 

Summary of Evidence

Targeted genetic testing to confirm diagnosis of coagulation Factor V Leiden (FVL), and Prothrombin G20210A (F2) is appropriate in selected populations. Professional society support for testing is available in the form of published guidelines. The evidence is sufficient to determine the technology results in meaningful improvement in net health outcomes in a select population.

 

Recurrent Pregnancy Loss

Miscarriage is defined as spontaneous loss of pregnancy before the fetus reaches viability (i.e., 24 weeks gestation). Early pregnancy loss generally occurs prior to 20 weeks gestation. Sporadic pregnancy loss is nonconsecutive pregnancy loss that occurs randomly during a woman’s reproductive years. Recurrent pregnancy loss, also referred to as recurrent spontaneous abortion (RSA) or recurrent miscarriage, is defined as two or more failed pregnancies and may affect as many as 1–3% of childbearing women. 

 

The need for formal assessment and testing for recurrent pregnancy loss varies among individuals depending on age and personal choice, although traditionally couples are offered evaluation after three losses. Infertile couples who are in their fourth decade (i.e., age ≥40) may elect to be evaluated after two losses.

 

Potential Causes of Recurrent Pregnancy Loss 

Recurrent pregnancy loss is a heterogeneous condition and may result from several underlying factors, such as anatomic, hormonal, thrombotic, autoimmune, alloimmune, genetic, infectious or other unknown causes. The following conditions may be associated with recurrent pregnancy loss:

• Parental chromosomal anomalies and genetic disorders
• Autoimmune disorders (e.g., antiphospholipid syndrome, systemic lupus erythematosus)
• alloimmune disorders
• structural uterine anomalies (e.g., bicornuate uterus, uterine septum, fibroids, intrauterine adhesions)
• cervical incompetence
• endocrine disorders (e.g., polycystic ovarian disease, luteal phase defect, thyroid disease)
• prothrombotic states (e.g., antithrombin III deficiency, protein C or protein S deficiency/resistance, thrombocythaemia, factor V Leiden)
• infectious diseases
• embryotoxicity 

 

Inherited thrombophilic disorders are well-established causes of systemic thrombosis, and may be associated with an increased risk of pregnancy loss. Research shows that thrombophilic disorders are also found in 20% of women with normal pregnancies suggesting that additional risk factors may be required for complications to develop. The most common inherited thrombotic disorders are factor V Leiden and prothrombin G20210A mutation. Other, less common deficiencies include anticoagulant protein C, protein S, antithrombin III and methylene tetrahydrolfolate reductase (MTHFR) gene. The scientific literature reports inconsistent findings for supporting any association with inherited thrombophilic disorders and recurrent early pregnancy loss, although some studies have shown a relationship with late pregnancy complications. A combination of thromobophilias may further increase the risk for recurrent fetal loss, and identification of one or more of the more common thrombophilias in a woman with RSA may warrant further investigation for other risk factors. However, the probability of having a successful pregnancy outcome remains high despite the presence of thrombophilic disorders. Routine screening of all pregnant women is not recommended. Decisions on testing and prophylactic treatment for thrombophilic disorders are based on a risk/benefit assessment.

 

ACOG does not recommend testing for inherited thrombophilias for women with recurrent fetal loss. According to a ACOG Practice Bulletin (2018) although there may be an association in these cases, the evidence is insufficient to support that antepartal prophylaxis with unfractionated heparin or LMWH prevent recurrence. ACOG specifically notes that concerning inherited thrombophilias in pregnancy, there is no definitive causal link between inherited thrombophilias and adverse pregnancy outcomes. Most of the available studies are small case-control and cohort studies assembled in heterogeneous populations, are frequently contradictory, and display potential reporting biases. Furthermore, ACOG does not recommend screening with fasting homocysteine levels because there is a lack of association between testing results and negative pregnancy outcomes. 

 

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 physician’s 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.

 

A Cochrane review reported that the evidence for safety and efficacy of thromboprophylaxis with aspirin and heparin for women with a history of at least two spontaneous miscarriages without apparent causes other than inherited thrombophilia. is too limited to recommend the use of anticoagulants in this setting. There is a paucity of studies evaluating efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia. The two trials reviewed evaluated different treatments and only one study was placebo-controlled. Neither of the studies showed a benefit of one treatment over the other. The Cochrane group indicated that further randomized clinical trials are needed.

 

Summary of Evidence

Based on evidence in the published, peer-reviewed scientific literature, a practice bulletin from ACOG, and other professional specialty organizations, the clinical utility of testing for inherited thrombophilia disorders is not recommended for unexplained early recurrent pregnancy loss. Although there may be an association with pregnancy loss that occurs after the first trimester, the clinical utility of screening in this population and benefit of treatment remains unclear. The evidence is insufficient in determining the technology improves net health outcomes. 

 

Methylenetetrahydrofolate Reductase (MTHFR) Gene Variations

The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a form of folate called 5,10-methylenetetrahydrofolate to a different form of folate called 5-methyltetrahydrofolate. This is the primary form of folate found in blood and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

 

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 has been associated with increased risk of homocystinuria, genetic testing is not indicated because these variants are not associated with thromboembolism.

 

Genotyping for MTHFR variations, including targeted variations analysis, carrier testing, prenatal testing, and full sequence analysis is available in clinical laboratories. 

 

Summary of Evidence 

Several variants of the MTHFR gene have been associated with increased risk of developing a number of conditions, however, 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 MTHFR genetic testing and its impact on net health outcomes. Professional society consensus support for MTHFR genotyping is limited. At this time the role of genetic testing for MTHFR has not been established. The evidence is insufficient in determining this technology results in net health outcomes.

 

Practice Guidelines and Position Statements

American College of Chest Physicians (ACCP)

In 2012, the American College of Chest Physicians (ACCP) published The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines that provides treatment guidelines for the circumstance when a pregnant woman is known to be homozygous for FVL or the prothrombin 20210A variant.

 

American College of Medical Genetics and Genomics (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 has 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. 

 

In 2018, the 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:

• A first unprovoked VTE, especially <50 years old
• VTE at unusual sites (such as hepatic portal, mesenteric, and cerebral veins)
• Recurrent VTE
• Personal history of VTE with (a) two or more family members with a history of VTE or one first-degree relative with VTE at a young age
• Patients with low activated protein C (APC) resistance activity  

 

Testing may also be considered in the following circumstances:

• Females under the age of 50 who smoke tobacco and have a history of acute myocardial infarction
• Siblings of individuals known to be homozygous for factor V Leiden or factor II c. *97G>A, because they have a 1 in 4 chance of being a homozygote
• Asymptomatic pregnant female or female contemplating pregnancy, with a first-degree relative with unprovoked VTE or VTE provoked by pregnancy or contraceptive use
• Pregnant female or female contemplating pregnancy or estrogen use who has a first-degree relative with a history of VTE and is a known carrier for factor V Leiden and/or factor II c.98*G>A variant
• Pregnant female or female contemplating pregnancy with a previous non-estrogen related VTE or VTE provoked by a minor risk factor, because knowledge of the factor V Leiden or factor II c.*97G>A status may alter pregnancy related thrombophylaxis 

 

Testing is not recommended for the following:

• A general population screen
• A prenatal or newborn test, or as a routine test in asymptomatic children
• A routine initial test in individuals with arterial thrombosis (testing may be considered, however, in selected young individuals [under age 50] with unexplained arterial thrombosis in the absence of other risk factors for atherosclerotic vascular disease) 

 

The American College of Obstetricians and Gynecologists (ACOG) 

The American College of Obstetricians and Gynecologists (2013) published management guidelines for inherited thrombophilias in pregnancy, which were reaffirmed in 2014 and in 2018. Screening for inherited thrombophilias is useful only when results will affect management decisions and is not useful in situations where treatment is indicated for other risk factors. Targeted assessment may be considered in the following clinical settings:

• A personal history of VTE associated with a nonrecurrent risk factor (e.g., fracture, surgery, or prolonged immobilization).
• A first-degree relative (e.g., parent, sibling) with a history of high-risk thrombophilia. 

 

Recommendations

Recommendations based primarily on consensus and expert opinion note screening for inherited thrombophilias should include FVL mutation; prothrombin G20210A mutation; and antithrombin, protein C, and protein S deficiencies. Additionally all patients with inherited thrombophilias should undergo individualized risk assessment, which may modify management decisions.

• Testing for inherited thrombophilias should include FVL, prothrombin G20210A mutation, and tests for deficiencies in antithrombin, protein S and protein C. Grade of Evidence: C;   Level of Evidence: Consensus and expert opinion
• 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. Grade of Evidence B; Level of Evidence: Limited or inconsistent scientific evidence
• Because an association between either heterozygosity or homozygosity for the MTHFR C677T polymorphism and any negative pregnancy outcomes, including any increased risk for VTE, has not been shown, screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended. Grade of Evidence: B; Level of Evidence: Limited or inconsistent scientific evidence.

 

Recommendations based primarily on consensus and expert opinion note screening for inherited thrombophilias should include FVL mutation; prothrombin G20210A mutation; and antithrombin, protein C, and protein S deficiencies. Additionally, all patients with inherited thrombophilias should undergo individualized risk assessment, which may modify management decisions.

 

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). 

 

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Commercial thrombophilia genetic tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.

 

Other commercial laboratories may offer a variety of functional assays and genotyping tests for F2 (prothrombin, coagulation factor II) and F5 (coagulation factor V), and single or combined genotyping tests for MTHFR.

 

Prior Approval:

Not applicable

 

Policy:

See Related Medical Policies

• 02.04.04 Cardiovascular Disease Risk Tests
• 02.04.67 Pharmacogenomic and Pharmacogenetic Testing for Drug Metabolism Status 
• 02.04.79 Circulating Tumor DNA for Management of Non-Small Cell Lung Cancer (Liquid Biopsy)
• 02.04.78 Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer

 

MTHFR

Genetic testing for variations in the MTHFR gene for all indications, including testing for thrombophilia or recurrent pregnancy loss is considered investigational. The evidence is insufficient in determining the technology improves net health outcomes.

 

Factor V Leiden (FVL)

Genetic testing with targeted mutation analysis for coagulation Factor V Leiden (FVL) may be considered medically necessary for an individual with an abnormal activated protein C (APC) resistant assay result and ANY of the following indications: 

1. An asymptomatic female who is planning pregnancy or is currently pregnant and not taking anticoagulation therapy and either of the following:
1. First-degree blood relative (i.e., parent, full-sibling or child) with a history of high-risk thrombophilia (e.g., antithrombin deficiency, double heterozygosity or homozygosity for FVL or prothrombin G202010A); or
2. First-degree blood relative (i.e., parent, full-sibling, child) with venous thromboembolism (VTE) before age 50 years; or
2. First unprovoked (e.g., from an unknown cause) venous thrombosis (VTE) at any age (especially age less than 50 years); or
3. Individual with first venous thrombosis (VTE) AND a first-degree blood relative (i.e., parent, full-sibling, child) with a VTE occurring before age 50 years: or
4. Individual with history of recurrent venous thrombosis (VTE); or 
5. Venous thrombosis (VTE) at unusual sites (e.g., cerebral, mesenteric, portal and hepatic veins); or 
6. Venous thrombosis (VTE) associated with the use of oral contraceptives or hormone replacement therapy (HRT); or 
7. Venous thrombosis (VTE) during pregnancy or the puerperium (the period of about six weeks after childbirth).

 

Prothrombin G20210A (F2 Gene)

Genetic testing with targeted mutation analysis for Prothrombin G20210A (F2 Gene) may be considered medically necessary for an individual for any of the following indications: 

1. An asymptomatic female who is planning pregnancy or is currently pregnant and not taking anticoagulation therapy and either of the following:
1. First-degree blood relative (i.e., parent, full-sibling or child) with a history of high-risk thrombophilia (e.g., antithrombin deficiency, double heterozygosity or homozygosity for FVL or prothrombin G202010A); or
2. First-degree blood relative (i.e., parent, full-sibling, child) with venous thromboembolism (VTE) before age 50 years; or
2. First unprovoked (e.g., from an unknown cause) venous thrombosis (VTE) at any age (especially age less than 50 years); or
3. Individual with first venous thrombosis (VTE) AND a first-degree blood relative (i.e., parent, full-sibling, child) with a VTE occurring before age 50 years: or
4. Individual with history of recurrent venous thrombosis (VTE); or
5. Venous thrombosis (VTE) at unusual sites (e.g., cerebral, mesenteric, portal and hepatic veins); or
6. Venous thrombosis (VTE) associated with the use of oral contraceptives or hormone replacement therapy (HRT); or
7. Venous thrombosis (VTE) during pregnancy or the puerperium (the period of about six weeks after childbirth). 

 

Genetic testing with targeted mutation analysis for Prothrombin G20210A (F2 Gene) or for coagulation Factor V Leiden is considered investigational for ANY of the following indications, because the effectiveness for indications other than the ones listed above has not been established:

• Not meeting the above criteria
• General population screening
• Recurrent pregnancy loss
• Newborn testing or routine testing in an asymptomatic child
• Routine initial testing in an individual with arterial thrombosis
• Testing of an asymptomatic first-degree blood relative (parent, full-sibling or child) of an individual with proven symptomatic venous thrombosis (VTE) and a proven coagulation Factor V Leiden or Prothrombin G20210A (F2 Gene) variant, for the purpose of considering prophylactic anticoagulation (except as noted above)
• Neonate or child with asymptomatic central venous catheter-related thrombosis 

 

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
• 81400 MOLECULAR PATHOLOGY PROCEDURE LEVEL 1 (includes F2 (coagulation factor 2) (eg, hereditary hypercoagulability), 1199G>A 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, 9^th 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.
• American College of Obstetricians and Gynecologists. Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy. Obstet Gynecol. 2018 Jul;132(1):e18-e34. PubMed PMID: 29939939.
• 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, 9^th 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, 9^th 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 
• Zhang, Shulin & K. Taylor, Annette & Huang, Xuan & Luo, Biao & Spector, Elaine & Fang, Ping & Sue Richards, C. (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). Genetics in Medicine. 10.1038/s41436-018-0322-z.
• Heit, John & Spencer, Frederick & H. White, Richard. (2016). The epidemiology of venous thromboembolism. Journal of Thrombosis and Thrombolysis. 41. 3-14. 10.1007/s11239-015-1311-6.
• Ansell J. E. (2016). Management of venous thromboembolism: clinical guidance from the Anticoagulation Forum. Journal of thrombosis and thrombolysis, 41(1), 1–2. doi:10.1007/s11239-015-1320-5
• Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 Update. Clin Pharmacol Ther. 2018 Feb;103(2):210-216. PubMed PMID: 29152729.
• Ashraf N, Visweshwar N, Jaglal M, Sokol L, Laber D. Evolving paradigm in thrombophilia screening. Blood Coagul fibrinolysis. 2019 May 24. [Epub ahead of print] PubMed PMID: 31145103
• UpToDate. Evaluating Adult Patients with Established Venous Thromboembolism for Acquired and Inherited Risk Factors. Kenneth A. Bauer M.D., Gregory YH Lip M.D., FRCPE, FESC, FACC. Topic last updated May 27, 2020.
• UpToDate. Screening for Inherited Thrombophilia in Asymptomatic Adults. Kenneth A. Bauer M.D., Topic last updated August 14, 2019.
• UpToDate. Inherited Thrombophilias in Pregnancy. Charles J. Lockwood M.D., MHCM, Kenneth A. Bauer M.D., Topic last updated March 31, 2021.
• UpToDate. Recurrent pregnancy loss: Evaluation. Tulandi T, Al-Fozan HM. Last updated October 21, 2019.
• American College of Chest Physicians. Antithrombotic therapy and prevention of thrombosis. Ninth edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Quick reference guideline for physicians. 2012 by the American College of Chest Physicians.  
• American College of Obstetricians and Gynecologists (ACOG). Early Pregnancy Loss. Practice Bulletin 200. November 201
• Croles FN, Nasserinejad K, Duvekot JJ, Kruip MJ, Meijer K, Leebeek FW. Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and Bayesian meta-analysis. BMJ. 2017 Oct 26;359
• Rühle F, Stoll M. Advances in predicting venous thromboembolism risk in children. Br J Haematol. 2018 Mar;180(5):654-665
• van Ommen CH, Nowak-Göttl U. Inherited Thrombophilia in Pediatric Venous Thromboembolic Disease: Why and Who to Test. Front Pediatr. 2017 Mar 14;5:50

 

Policy History:

• May 2021 - Annual Review, Policy Revised
• May 2020 - Annual Review, Policy Revised
• May 2019 - Annual Review, Policy Revised
• 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 

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.