Medical Policy: 02.04.46 

Original Effective Date: September 2013 

Reviewed: May 2020 

Revised: May 2020 

 

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:

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.

 

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. 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.

 

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.

 

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).

 

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. 

 

American College of Medical Genetics and Genomics (ACMG, 2018)

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 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 

 

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. 

 

The Anticoagulation Forum published guidance in the Journal of Thrombosis and Thrombolysis (2016):

Do not perform thrombophilia testing following an episode of provoked VTE.

  • A positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE. 

 

Do not perform thrombophilia testing in patients following an episode of unprovoked VTE.

  • If a patient with unprovoked VTE and low bleeding risk is planning to stop anticoagulation, test for thrombophilia if test results would change this decision. A negative thrombophilia evaluation is not a sufficient basis to stop anticoagulants following an episode of unprovoked VTE in a patient with low bleeding risk and willingness to continue therapy. Heterozygosity for FVL or PGM does not increase the predicted risk of recurrence after unprovoked VTE to a clinically significant degree. 

 

Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia.

  • As a family history of VTE confers an excess risk of thrombosis, relatives should be counseled regarding use of prophylaxis in high risk situations.
  • Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia who are contemplating use of estrogen. 

 

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.

 

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 Validity

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

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.

 

Summary of Evidence

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).

 

Regulatory Status

Genetic Tests for Thrombophilia Cleared by the Food and Drug Administration (FDA)
TestManufacturer
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

 

Prior Approval:

Not applicable

 

Policy:

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:

  • 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.

  

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.

 

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
  • 81401 MOLECULAR PATHOLOGY PROCEDURE LEVEL 2

 

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.
  • 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, 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 
  • 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

 

Policy History:

  • 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.