Coverage Policy Manual
Policy #: 2007018
Category: Laboratory
Initiated: November 2007
Last Review: August 2018
  Genetic Test: Inherited Thrombophilia, Prothrombin Gene Mutations (G20210A) and MTHFR Mutations

Description:
Inherited thrombophilias are a group of disorders that predispose to thrombosis. Genetic testing is available for some of these disorders and could potentially assist in the diagnosis and/or management of patients with thrombosis.
 
Background
 
Venous thromboembolism. The overall U.S. incidence of venous thromboembolism (VTE) is approximately 1 per 1,000 person-years, and the lifetime clinical prevalence is about 5%, accounting for 100,000 deaths annually (Heit, 2001). Risk is strongly age-related, with the greatest risk in older populations. VTE also recurs frequently; the estimated cumulative incidence of first VTE recurrence is 30% at 10 years (Heit, 2001). These figures do not separate patients who had known predisposing conditions from those who do not.
 
Risk factors for thrombosis include a variety of clinical and demographic variables, and at least one risk factor can be identified in approximately 80% of patients with a thrombosis. The following list includes the most important risk factors:
 
  • Malignancy
  • Immobility
  • Surgery
  • Obesity
  • Pregnancy
  • Hormonal therapy with estrogen/progesterones
  • Systemic lupus erythematosus (SLE), and/or other rheumatologic disorders
  • Myeloproliferative disorders
  • Liver dysfunction
  • Nephrotic syndrome
  • Hereditary factors
 
Treatment of thrombosis involves anticoagulation for a minimum of 3 to 6 months. Following this initial treatment period, patients deemed to be at a continued high risk for recurrent thrombosis may be continued on anticoagulation for longer periods, sometimes indefinitely. Anticoagulation is effective in reducing the subsequent risk of thrombosis, but has its own risks of bleeding.
 
Pregnancy is often considered a special condition because of its frequency and the unique considerations of preventing and treating VTE in this setting. Pregnancy is associated with a 5-10-fold increase in the risk for VTE, and the absolute risk of VTE in pregnancy has been estimated to be 1-2 per 1,000 deliveries (Baglin, 2010). In women with a previous history of pregnancy-related VTE, the risk of recurrent VTE with subsequent pregnancies is increased greatly at approximately 100-fold (Baglin, 2010).
 
Inherited thrombophilia. Inherited thrombophilias are a group of clinical conditions in which there is a genetic variant defect 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 an individual’s risk of VTE.
 
There are a number of conditions that fall under the classification of inherited thrombophilias, which arise from genetic variants in the genes involved in defects in the coagulation cascade. Inherited thrombophilias include the following abnormalities:
 
  • Activated protein C resistance (factor V Leiden mutations)
  • Prothrombin gene mutation
  • Protein C deficiency
  • Protein S deficiency
  • Prothrombin deficiency
  • Hyper-homocysteinemia (MTHFR mutations)
 
The most common type of inherited thrombophilia is a factor V Leiden mutation (see policy #2004044), which accounts for up to 50% of the inherited thrombophilia syndromes. In unselected patients with an idiopathic thrombosis, the rate of factor V Leiden positivity is in the range of 17-24%, (Bauer, 2011) compared to a rate of 5-6% in normal controls. The prothrombin gene mutation is found less commonly, in approximately 5-8% of unselected patients with thrombosis, compared to 2-2.5% of normal controls (Bauer, 2011).
 
Genetic testing for gene variants associated with thrombophilias is available for factor V Leiden, the prothrombin gene mutation, and the MTHFR gene. The use of genetic testing for inherited thrombophilia can be considered in several clinical situations. The clinical situations that will be addressed in this policy include the following:
 
  • Assessment of the risk for thrombosis in asymptomatic patients (screening for inherited thrombophilia)
  • Evaluation of a patient with established thrombosis, in consideration of change in anticoagulant management based on results
  • Evaluation of close relatives of patients with documented inherited thrombophilia, or with a clinical and family history that is consistent with an inherited thrombophilia
  • Evaluation of patients in other situations that are considered high risk for thrombosis, e.g. pregnancy, planned major surgery, or oral contraceptive use.
 
Regulatory Status
More than a dozen commercial laboratories currently offer a wide variety of diagnostic procedures for F2 (prothrombin, coagulation factor II), F5 (coagulation factor V), and MTHFR (5, 10-methylenetetrahydrofolate reductase) genetic testing. These tests are available as laboratory developed procedures under the U.S. Food and Drug Administration (FDA) enforcement discretion policy for laboratory developed tests.
 
Coding
 
Specific CPT codes for this testing became available in 2012:
 
81240: F2 (prothrombin, coagulation factor II)(e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant
 
81291: MTHFR (5, 10-methylenetetrahydrofolate reductase)(e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)
 
 
Genetic testing for Factor V Leiden is addressed in a separate policy #2004044.
 
 

Policy/
Coverage:
Effective October 2013
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for prothrombin thrombophilia with G20210A meets primary coverage criteria for effectiveness and is covered for:
    • Patients with a first venous thromboembolism (VTE), age < 50 years except when active malignancy is present;
    • Patients with a first, unprovoked VTE at any age except when active malignancy is present
    • Patients with a history of recurrent VTE
    • Patients with venous thrombosis  at unusual sites such as the cerebral, mesenteric, portal or hepatic veins
    • Patients with first VTE at any age with a first-degree family member with a VTE before age 50
    • Women whose pregnancy ends with fetal death after 10 weeks gestation and who have a family history of thromboembolism
    • Women with recurrent fetal loss, two or more consecutive pregnancy losses
    • Women who have VTE during pregnancy or in the postpartum period
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for prothrombin thrombophilia with G20210A for any indication other than those specifically listed as covered will be denied based on Primary Coverage Criteria requiring interventions must be proven to be effective in treating, diagnosing, detecting, or palliating a medical condition.  Medical literature is not consistent regarding testing for any other indications nor is there evidence of a positive effect on health outcomes.
 
Testing for mutations in the MTHFR gene does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
 
For members with contracts without primary coverage criteria, testing for mutations in the MTHFR gene is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to October 2013
Testing for prothrombin thrombophilia with G20210A meets primary coverage criteria for effectiveness and is covered for:
    • Patients with a first venous thromboembolism (VTE), age < 50 years except when active malignancy is present;
    • Patients with a first, unprovoked VTE at any age except when active malignancy is present
    • Patients with a history of recurrent VTE
    • Patients with venous thrombosis  at unusual sites such as the cerebral, mesenteric, portal or hepatic veins
    • Patients with first VTE at any age with a first-degree family member with a VTE before age 50
    • Women whose pregnancy ends with fetal death after 10 weeks gestation and who have a family history of thromboembolism
    • Women with recurrent fetal loss, two or more consecutive pregnancy losses
    • Women who have VTE during pregnancy or in the postpartum period
 
Testing for prothrombin thrombophilia with G20210A for any indication other than those specifically listed as covered will be denied based on Primary Coverage Criteria requiring interventions must be proven to be effective in treating, diagnosing, detecting, or palliating a medical condition.  Medical literature is not consistent regarding testing for any other indications nor is there evidence of a positive effect on health outcomes.

Rationale:
Group contracts furnished or renewed on or after July 1, 2004 or individual contracts furnished on or after July 1, 2004 have the following coverage for genetic testing:
    • Services for genetic testing to determine the likelihood of developing disease or condition, the likelihood of a disease or the presence of a disease in a relative, or the likelihood of passing an inheritable disease or congenital abnormality to an offspring, are not covered.
    • Services for pre-implantation genetic diagnosis or treatment are not covered.
    • However, subject to all terms, conditions, exclusions and limitations of the Plan set forth in this Benefit Certificate, genetic testing of the products of an amniocentesis, to determine the presence of a disease or congenital anomaly in the fetus, or genetic testing of a Covered Person’s tissue to determine if the Person has a specific disease (not to determine if the person is a carrier of a genetic abnormality), is covered.  See Subsection dealing with Pre-Natal Tests.]
 
No clinical features are specific for prothrombin thrombophilia. The diagnosis of prothrombin thrombophilia requires DNA analysis of F2, the gene encoding prothrombin, to identify the common mutation, a G>A transition at nucleotide 20210.  Prothrombin thrombophilia should be suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep-vein thrombosis (DVT) or pulmonary embolism, especially those with a personal or family history of recurrent thrombosis at a young age.
 
Ho et al concluded “while patients with recurrent VTE are more likely to have heterozygous FVL or prothrombin G20210A than those without recurrence, the magnitude of increased risk is modest.  Therefore, in the absence of other risk factors, the presence of either FVL or prothrombin G20210A alone is unlikely to merit extended-duration anticoagulation.  This calls into question the cost-effectiveness of routine testing for these common inherited thrombophilic disorders in patients with a first episode of VTE.”
 
No clinical features are specific for prothrombin thrombophilia. The diagnosis of prothrombin thrombophilia requires DNA analysis of F2, the gene encoding prothrombin, to identify the common mutation, a G>A transition at nucleotide 20210.  Prothrombin thrombophilia should be suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep-vein thrombosis (DVT) or pulmonary embolism, especially those with a personal or family history of recurrent thrombosis at a young age.  Ho et al  (2006) concluded “while patients with recurrent VTE are more likely to have heterozygous FVL or prothrombin G20210A than those without recurrence, the magnitude of increased risk is modest.  Therefore, in the absence of other risk factors, the presence of either FVL or prothrombin G20210A alone is unlikely to merit extended-duration anticoagulation.  This calls into question the cost-effectiveness of routine testing for these common inherited thrombophilic disorders in patients with a first episode of VTE.”
 
In a review article Middeldorp et. al. (2008) state the association between hereditary thrombophilia and fetal loss, preeclampsia, or intra-uterine growth retardation is unknown to be causal and is controversial.   “We conclude that testing for hereditary thrombophilia generally does not alter the clinical management of patients with venous or arterial thrombosis or pregnancy complications.”
 
2011 Update
Clinical Utility:
The clinical utility of a direct diagnostic genetic test for the detection of the presence of G20210A alleles (DNA analysis of the F2 gene) in patients suspected of having Prothrombin Thrombophilia has been found to have little, if any, risks associated with it, and the benefits of this test can be invaluable in this selected population of patients.
 
New York State Validation Program:
Currently there is evidence that at least one laboratory performing genetic testing for G20210A alleles (DNA analysis of the F2 gene) has been validated by the New York State Validation program (Wadsworth Center).
 
Clinical Appropriateness:
Genetic testing for G20210A alleles (DNA analysis of the F2 gene) in applicable patients is deemed appropriate and necessary in selected cases at this juncture.
 
EGAPP:
In January 2011, the EGAPP Working Group published recommendations on the routine testing of Factor V Leiden (R506Q) (FVL) and prothrombin (20210G>A) (PT) mutations in adults with a history of idiopathic venous thromboembolism.  The EGAPP working group was organized to conduct an evidence-based review to make a decision on the clinical utility of testing for FVL mutations alone or in combination with PT mutation testing.  The group recommended against routine testing of FVL and PT in adults with idiopathic venous thromboembolism and the asymptomatic relatives of patients with VTE and a Factor V Leiden or PT mutation.  
 
The group found that the evidence suggests that prophylaxis to avoid a recurrence of VTE yields the same results in patients with and without one or more of these mutations.  In asymptomatic family members, the benefits of prophylaxis are unlikely to outweigh the potential harms.  The group reports that there have been no prophylaxis trials in asymptomatic family members and there is no direct evidence that prophylaxis is of any benefit to family members of patients with VTE and an FVT and/or PT mutation.
  
 
Gene Reviews:
Gene testing for the presence of G20210A Alleles (DNA analysis of the F2 gene) has been evaluated by Gene Reviews, and currently there is a full complement of information on this testing modality available on the Gene Reviews web site. A full list of laboratories that perform this testing modality is also present on the Gene Reviews website.
 
American College of Medical Genetics:
Gene testing for the presence of G20210A Alleles (DNA analysis of the F2 gene) is not currently listed on the website of the American College of Medical Genetics. There is currently no information on the bulletin board on the web site of the ACMG concerning Prothrombin Thrombophilia.
 
Hayes Inc Assessment:
Hayes Inc. Assessment states that gene testing for the presence of G20210A Alleles (DNA testing for the F2 gene) has been evaluated and assessed, and Hayes gives a B rating (Some proven benefit) to this genetic testing modality both in patients with VTE with a personal or family history of recurrent VTE and in patients with obstetric complications of abnormal placenta vasculature.
 
2012 Update
A literature search was conducted through September 2012.  There was no new randomized trials, practice guidelines, position statements or other publications identified that would prompt a change in the coverage statement.
 
2013 Update
A literature search was conducted through September 2013. The policy is revised to include new information and address MTHFR mutation testing. The following is a summary of key literature identified.
 
MTHFR Mutation Testing
Mutations in the MTHFR gene are associated with hyperhomocysteinemia, which is in turn associated with an increased risk for venous thromboembolism (VTE). However, the clinical utility of testing for homocysteine levels has not been established. There is a large literature base on the association of homocysteine levels with coronary artery disease (CAD), and clinical trials on the impact of lowering homocysteine levels. This body of evidence indicates that testing or treating for homocysteinemia is not associated with improved outcomes.
 
For the association of MTHFR with VTE, the evidence is not definitive. Some studies have shown an association, but others have not. In one of the larger studies, the MEGA study, there was no association of the MTHFR mutation with recurrent VTE (Bezemer, 2007).  A randomized controlled trial (RCT) published in abstract form reported that there was no reduction in VTE associated with treatment of hyperhomocysteinemia (den Heijer, 2007).
 
Conclusions. There is limited published evidence on the utility of testing for MTHFR mutations in patients with VTE or at risk for VTE. Given the available literature, and the lack of clinical utility for serum homocysteine testing in general, it is unlikely that testing for the MTHFR gene will improve outcomes.
 
Prothrombin Mutation Testing
There was no new information identified that would prompt a change in the coverage statement for prothrombin mutation testing. The following is a summary of the key identified literature since the last policy update.
 
A 2012 systematic review by Bradley et al. (Bradley, 2012) analyzed the evidence on the association of FVL and prothrombin mutations with pregnancy loss. These authors identified the highest quality studies, which were cohort studies that: 1) excluded patients with other causes of VTE, 2) tested eligible women for thrombophilia at baseline, 3) reported on subsequent pregnancy outcomes, and 4) compared rates of pregnancy loss between carriers and non-carriers. Four cohort studies met all these criteria; these studies primarily included patients with FVL mutations. Two of the 4 studies reported a significantly increased rate of recurrence for carriers, and 2 studies did not. Combined analysis of these 4 studies yielded a significantly increased odds ratio (OR) for recurrence of pregnancy loss in carriers (OR: 1.93, 95% CI: 1.21-3.09).
 
This review (Bradley, 2012) evaluated the analytic validity in individual studies and meta-analyses in the setting of pregnancy-related testing. For studies performed in the U.S., the combined analytic sensitivity and specificity for FVL testing was greater than 99%. For the prothrombin mutation, the analytic sensitivity was 98.4% and the analytic specificity was 99.7%.
 
The American College of Obstetricians and Gynecologists published clinical management guidelines for inherited thrombophilias in pregnancy in 2010 (ACOG, 2010). These guidelines stated that testing for inherited thrombophilias is controversial, but could be considered for pregnant women in the following situations:
 
  • A personal history of venous thromboembolism that was associated with a nonrecurrent risk factor (e.g., fractures, surgery, and prolonged immobilization).
  • A first-degree relative with a history of high-risk thrombophilia or venous thromboembolism before age 50 years in the absence of other risk factors in as much as affected women should receive prophylaxis.
   
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Mutations in the MTHFR gene are associated with hyperhomocysteinemia, which is in turn considered a weak risk factor for VTE (ACOG, 2013) However, clinical utility of testing for homocysteine levels has not been established. There is a large body of literature on the association of homocysteine levels with coronary artery disease (CAD), and clinical trials have assessed the impact of lowering homocysteine levels. This body of evidence indicates that testing or treating for homocysteinemia is not associated with improved outcomes.
 
Evidence for the association of MTHFR with VTE is not definitive. Some studies have shown an association (Russo, 2014; Supanc, 2024; Zhou, 2013; Li, 2014) but others have not. (Joachim, 2013; Chatterjee, 2013). One larger study (N=9231), the 2007 MEGA study, showed no association between the MTHFR mutation with recurrent VTE.  A randomized controlled trial (RCT) reported no reduction in VTE associated with treatment of hyperhomocysteinemia.
 
Mahajerin et al (2014) conducted a single-center, retrospective cohort study of pediatric patients (mostly adolescents) who presented with VTE (88% DVT) “to help clarify the role of thrombophilia testing in pediatric VTE” (Mahajerin, 2014). Of 392 inpatients and outpatients, thrombophilia tests (FVL; prothrombin gene mutation; MTHFR; protein C, protein S, and antithrombin activity; antiphospholipid antibodies; plasminogen activator inhibitor-1 levels and mutation testing) were ordered in 310 (79%); of these, positive results returned in 37 (12%). Given that most patients had at least 1 risk factor for VTE and, as noted by the authors, “presence or absence of thrombophilia rarely influences VTE management,” this evidence does not support thrombophilia genetic testing in pediatric patients who present with VTE.
 
In 2012, ACCP published the ninth edition of their evidence-based guidelines on antithrombotic therapy and the prevention of thrombosis (Guyatt, 2012). For pregnant women with no prior history of VTE who are known to be homozygous for factor V Leiden (FVL) or the prothrombin G20210A mutation, ACCP made the following recommendations:
  • Positive family history for VTE: ACCP suggests antepartum prophylaxis with prophylactic- or intermediate-dose low molecular weight heparin (LMWH) and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or warfarin (international normalized ratio [INR] target, 2.0-3.0) rather than no prophylaxis (Grade 2B [weak] recommendation, based on moderate-quality evidence)
  • No family history for VTE: ACCP suggests antepartum clinical vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or warfarin (INR target, 2.0-3.0) rather than routine care (Grade 2B recommendation).
 
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. The following are examples of U.S. guidelines developed by major specialty societies and published in the last 5 years.
 
American College of Obstetricians and Gynecologists (ACOG)
ACOG published clinical management guidelines for inherited thrombophilias in pregnancy in 2013 (ACOG, 2013).These guidelines stated that a definitive causal link between inherited thrombophilias and adverse pregnancy outcomes cannot be made. Screening for inherited thrombophilias is controversial, but may be considered for pregnant women in the following situations:
  • A personal history of venous thromboembolism that was associated with a nonrecurrent risk factor (eg, fracture, surgery, or prolonged immobilization).
  • A first-degree relative (eg, parent, sibling) with a history of high-risk thrombophilia
The guidelines also state that:
  • Testing for inherited thrombophilias should include FVL, prothrombin G20210A mutation, and tests for deficiencies in antithrombin, protein S and protein C (Level C recommendation, based primarily on 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 (Level B recommendation, based on 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 (Level B recommendation).
 
U.S. Preventive Services Task Force (USPSTF)
USPSTF recommendations for genetic testing for thrombophilia were not identified.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
The current chapter on prothrombin-related thrombophilia in GeneReviews® concluded: “Although technically possible, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are rarely, if ever, performed because the 20210G>A allele only increases the relative risk for thrombophilia and is not predictive of a thrombotic event (Kujovich, 2011).
 
Ongoing and Unpublished Clinical Trials
One currently unpublished trial that might influence this policy
 
NCT02385461 Proposal of a Prospective Study on Prevention of Pregnancy Loss in Women Carrying Inherited Thrombophilia; planned enrollment 108; projected completion date June 2017.
 
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Pregnancy and Other High-Risk Conditions
No studies have directly evaluated the clinical utility of thrombophilia testing in pregnant women. The clinical utility of testing depends on the efficacy of potential treatments in decreasing fetal loss versus the risks of treatment. Potential treatments in pregnancy include aspirin, low-dose unfractionated or low-molecular- weight heparin, and full-dose heparin. Benefits of these treatments in reducing pregnancy loss are questionable. At least 2 RCTs (both 2010) have reported that there is no significant reduction in risk with aspirin or heparin therapy (Clark, 2010; Kaandorp, 2010). Additionally, several meta-analyses have reported that evidence is insufficient to conclude that these interventions reduce recurrent pregnancy loss in patients with FVL or prothrombin variants (Bradley, 2012; Skeith, 2016; de Jong, 2014).\l "\l " In contrast, the real risks of anticoagulation include bleeding, thrombocytopenia, and allergic reactions. There also are costs and inconvenience associated with these treatments.
 
Bradley and colleagues reviewed the evidence on the clinical utility of testing for heritable thrombophilias in pregnancy and found it adequate to conclude there are no safe and effective treatments to reduce recurrent pregnancy loss in women with inherited thrombophilia (Bradley, 2012). The certainty of the evidence that treatment resulted in net harm was moderate.
 
The clinical utility of testing for prothrombin-related thrombophilia was evaluated in a secondary analysis of data from the Stillbirth Collaborative Research Network, a population-based case-control study of stillbirth. Testing for FVL, prothrombin G20210A, methylenetetrahydrofolate reductase C677T, and A1298C, and plasminogen activating inhibitor-1 4G/5G variants was done on maternal and fetal (or placental) DNA from singleton pregnancies. There was an increased odds of stillbirth for maternal homozygous FVL variant (2/488 [0.4%] vs 1/1380 [0.0046%]; OR=87.44; 95% CI, 7.88 to 970.92). However, there were no significant differences in the odds of stillbirth for any other maternal thrombophilia, even after stratified analyses.31
An open-label, international, multicenter randomized trial (2014) of antepartum use of low-molecular weight heparin dalteparin included women with the prothrombin variant. The intervention did not reduce the occurrence of VTE, pregnancy loss, or placenta-mediated pregnancy complications, and was associated with an increased risk of minor bleeding.32
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing:
(NCT02841085) New Genetic Mutations in Thromboembolic Venous Disease; planned enrollment 450; projected completion date May 2018
 
(NCT02685800) Recurrent Failures in assisted Reproductive Techniques (The FIRST Registry); planned enrollment 624; projected completion date September 2018
 
(NCT02990403) The Novel Immunomodulatory and Anticoagulant Therapies for Recurrent Pregnancy Loss; planned enrollment 500; projected completion date December 2018
 
(NCT02407730) Effects of Thrombophilia on the Outcomes of Assisted Reproduction  Technologies; planned enrollment 715; projected completion date June 2019
 
(NCT02986594) Diagnosis and Treatment Strategy of Recurrent Spontaneous Abortion Associated with Thrombophilia; planned enrollment 600; projected completion date October 2019
 
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
81240F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G&gt;A variant
81291MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C)

References: ACOG. American College of Obstetrics and Gynecology.(2013) . Practice bulletin no. 138: inherited thrombophilias in pregnancy, September 2013. Available online at: http://www.acog.org/~/media/List%20of%20Titles/PBListOfTitles.pdf?dmc=1&ts=20140519T1 432297315. Last accessed June 2014.

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Bates SM, Greer IA, et al.(2008) Venous thromboembolism, thrombophilia, antithrombotic therapy and pregnancy. Chest, 2008; 133(6):

Bianca S, Barrano B, et al.(2008) Recurrent pregnancy loss and inherited thrombophilia: who should be tested? J Clin Pathol, 2008; 81:1149-50.

Bradley LA, Palomaki GE, Bienstock J, et al.(2012) Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med. Jan 2012;14(1):39-50. PMID 22237430

Brenner B, Aharon A.(2007) Thrombophilia and adverse pregnancy outcome. Clin Perinatol, 2007; 34:527-41.

Brenner BR, Nowak-Gottl U, et al.(2002) Diagnostic studies for thrombophilia in women on hormonal therapy and during pregnancy and in children. Arch Pathol Lab Med, 2002; 126:1296-1303.

Castoldi E, Simioni P, et al.(2007) Differential effects of high prothrombin levels on thrombin generation depending on the cause of the hyperprothrombinemia. Thromb Haemost, 2007; 5:971-9.

Chatterjee T, Gupta N, Choudhry VP et al.(2013) Prediction of ischemic stroke in young Indians: is thrombophilia profiling a way out? Blood Coagul Fibrinolysis 2013; 24(4):449-53.

Clark P, Walker ID, Langhorne P, et al.(2010) SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. May 27 2010;115(21):4162-4167. PMID 20237316

College of American Pathologists Consensus Conference XXXVI: Diagnostic issues in thrombophilia. Arch Pathol Lab Med, 2002; 126:1277-80.

Coulam CB, Jeyendran RS, et al.(2006) Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immun, 2006; 55:360-8.

Coulam CB, Wallis D, et al.(2008) Comparison of thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein throbosis. Am J Reprod Immunol, 2008; 60(5):426-31.

de Jong PG, Kaandorp S, Di Nisio M, et al(2014) Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. Jul 04 2014(7):CD004734. PMID 24995856

de Moerloose P, Bochlen F.(2007) Inherited thrombophilia in arterial disease: a selective review. Semin Hematol, 2007; 44(2):106-13.

De Moerloose P, Boehien F.(2007) Inherited thrombophilia in arterial disease: a selective review. Semin Hematol, 2007; 44:106-13.

De Stafano V, Rossi E, et al.(2006) Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia. Semin Thromb Hemost, 2006; 32:767-80.

DeStefano V, Rossi E, et al.(2006) Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia. Semin Thromb Hemost, 2006; 32(8):767-80.

EGAPP Working Group.(2011) Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med. Jan 2011;13(1):67-76. PMID 21150787

Eroglu A, Ulu A, et al.(2007) Prevalence of Factor V 1691 G-A (Leiden) and prothrombin G20210A polymorphisms and the risk of venous thrombosis among cancer patients. J Thromb Thrombolysis, 2007; 23(1):31-4.

Eroglu A, Ulu A, et al.(2007) Prevalence of Factor V 1691 G-A (Leiden) and prothrombin G20210A polymorphisms and the risk of venous thrombosis among cancer patients. J Thromb Thrombolysis, 2007; 23:31-4.

Gerhardt A, Scharf RE, et al.(2000) Prothrombin and Factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. NEJM, 2000; 342:374-80.

Goodman CS, Coulam CB, et al.(2006) Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss. Am J Reprod Immun, 2006; 56:230-6.

Grandone E, Coalizzo D, et al.(2006) More on: factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first-intended pregnancy: the matched case-control 'NOHA first' study. J Thromb Haemost, 2006; 4:709-10.

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