Medical Policy

Policy Num:     11.003.012
Policy Name:    Genetic Testing for Inherited Thrombophilia
Policy ID:          [11.003.012]  [Ac / B / M- / P-]  [2.04.82]

Last Review:       June 18, 2024
Next Review:      June 20, 2025
 

Related Policies:

11.001.022 Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease
 

Genetic Testing for Inherited Thrombophilia

Summary

Description

Inherited thrombophilias are a group of disorders that predispose individuals to thrombosis. Genetic testing is available for some of these disorders and could assist in the diagnosis and/or management of patients with thrombosis. For example, testing is available for types of inherited thrombophilia, including variants in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, the factor V gene (factor V Leiden [FVL] variant), and the prothrombin (factor II) gene.

Summary of Evidence

For individuals who are asymptomatic with or without a personal or family history of venous thromboembolism (VTE) or who are asymptomatic with increased VTE risk (eg, due to pregnancy) who receive genetic testing for variants in MTHFR, or genetic testing for coagulation factor V and coagulation factor II, the evidence includes a large randomized controlled trial, prospective cohort analyses, retrospective family studies, case-control studies, and meta-analyses. Relevant outcomes are morbid events and treatment-related morbidity. The clinical validity of genetic testing has been demonstrated by the presence of an FVL 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 (OR) most commonly between 1 and 2, except for family members of individuals with inherited thrombophilia, for whom ORs are somewhat higher. The clinical utility of testing for FVL or prothrombin variants has not been demonstrated. Although the presence of inherited thrombophilia increases the risk for subsequent VTE events, the increase is modest, and the absolute risk of thrombosis remains low. Available prophylactic treatments (eg, anticoagulation) have defined risks of major bleeding and other adverse events that may outweigh the reduction in VTE and therefore result in net harm. Currently, available evidence has not defined a role for thrombophilia testing for decisions on initiation of prophylactic anticoagulation or the length of anticoagulation treatment. For MTHFR testing, clinical validity and clinical utility of genetic testing are uncertain. Because clinical utility of testing for elevated serum homocysteine itself has not been established, the utility of genetic testing also has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether genetic testing for 5,10-methylenetetrahydrofolate reductase, factor V gene, and prothrombin gene variants improves the net health outcome in individuals with inherited thrombophilias.

Policy Statements

Genetic testing for inherited thrombophilia, including testing for the factor V Leiden variant, prothrombin gene variants, and variants in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, is considered investigational.

Policy Guidelines

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Venous Thromboembolism

The overall U.S. incidence of venous thromboembolism (VTE) is approximately 1 to 2 per 1,000 person-years, and the lifetime clinical prevalence is approximately 8%.^1,After VTE, 1-year survival varies greatly by underlying VTE cause, with lower survival rates seen for cancer-associated VTE (~47%) and higher survival among patients with provoked (84%) or unprovoked (93%) VTE.The risk is strongly age-related, with the greatest risk in older populations. Venous thromboembolism also recurs frequently; the estimated cumulative incidence of first VTE recurrence is 30% at 10 years.^2,1, These figures do not separate patients with known predisposing conditions from those without.

Risk factors for thrombosis include clinical and demographic variables, and at least 1 risk factor can be identified in approximately 80% of patients with thrombosis. The following list includes the most important risk factors:

• Malignancy

• Immobility

• Surgery

• Obesity

• Pregnancy

• Hormonal therapy such as estrogen/progestin or selective estrogen modulator products

• Systemic lupus erythematosus and/or other rheumatologic disorders

• Myeloproliferative disorders

• Liver dysfunction

• Nephrotic syndrome

• Hereditary factors.

Pregnancy often is considered a special circumstance because of its frequency and unique considerations for preventing and treating VTE. Pregnancy is associated with a 5- to 10-fold increase in VTE risk, and absolute VTE risk in pregnancy is estimated to be 1 to 2 per 1000 deliveries.^3, In women with a history of pregnancy-related VTE, risk of recurrent VTE with subsequent pregnancies is increased greatly at approximately 100-fold.^3,

Treatment

Treatment of thrombosis involves anticoagulation for a minimum of 3 to 6 months. After this initial treatment period, patients deemed to be at a continued high risk for recurrent thrombosis may continue on anticoagulation therapy for longer periods, sometimes indefinitely. Anticoagulation is effective for reducing the subsequent risk of thrombosis but carries its own risk of bleeding.

Inherited Thrombophilia

Inherited thrombophilias are a group of clinical conditions characterized by genetic variant defects associated with a change in the amount or function of a protein in the coagulation system and a predisposition to thrombosis. Not all individuals 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 VTE risk.

A number of conditions fall under the classification of inherited thrombophilias. Inherited thrombophilias include the following conditions, which are defined by defects in the coagulation cascade:

• Activated protein C resistance (factor V Leiden [FVL] variant)

• Prothrombin (factor II) gene variant (G20210A)

• Protein C deficiency

• Protein S deficiency

• Prothrombin deficiency

• Hyper-homocysteinemia (5,10-methylenetetrahydrofolate reductase [MTHFR] variant).

The most common type of inherited thrombophilia is FVL, which accounts for up to 50% of inherited thrombophilia syndromes. Generally, routine testing for hypercoagulable disorders is not recommended in unselected patients.^4, For those considered at risk (eg, strong family history, recurrent thromboses), the prevalence of identifying an inherited thrombophilia ranges from 5% to 40%; the prevalence is estimated at 12% to 40% for FVL and 6% to 18% for prothrombin G20210A variant in this population.

Genetic Testing

Genetic testing for gene variants associated with thrombophilias is available for FVL, the prothrombin G20210A variant, and MTHFR. Genetic testing for inherited thrombophilia can be considered in several clinical situations. Clinical situations addressed herein include the following:

• Assessment of thrombosis risk in asymptomatic patients (screening for inherited thrombophilia);

• Evaluation of a patient with established thrombosis, for consideration of a change in anticoagulant management based on results;

• Evaluation of close relatives of patients with documented inherited thrombophilia or with a clinical and family history consistent with an inherited thrombophilia;

• Evaluation of patients in other situations who are considered at high-risk for thrombosis (eg, pregnancy, planned major surgery, exogenous hormone use).

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 (CLIA). Commercial thrombophilia genetic tests are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

The FDA has cleared several genetic tests for thrombophilia for marketing through the 510(k) process for use as an aid in the diagnosis of patients with suspected thrombophilia. Some of these tests are listed in Table 1.

Table 1. Genetic Tests for Thrombophilia Cleared by FDA

FDA: Food and Drug Administration.a FDA marketing clearance was granted to Sequenom Bioscience before it was acquired by Agena Bioscience.b FDA marketing clearance was granted to Osmetech Molecular Diagnostics.

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.

In November 2017, the 23andMe Personal Genome Service (PGS) Genetic Health Risk was granted a de novo classification by the FDA (class II with general and special controls, FDA product code: PTA). This is a direct-to-consumer test that has been evaluated by the FDA for accuracy, reliability, and consumer comprehension. This test reports whether an individual has variants associated with a higher risk of developing harmful blood clots. This report is based on a qualitative genetic test for single nucleotide polymorphism detection of Factor V Leiden variant in the F5 gene (rs6025) and Prothrombin G20210A variant in the F2 gene (rs1799963/i3002432). Similarly, in August 2020, Ancestry Genomics, Inc was granted the same de novo classification by the FDA (class II with general and special controls, FDA product code: PTA). This AncestryDNA Factor V Leiden Genetic Health Risk Test reports whether an individual has variants associated with a higher risk of developing harmful blood clots. This report is based on a qualitative genetic test for single nucleotide polymorphism detection of Factor V Leiden variant in the F5 gene (rs6025).

Rationale

This evidence review was created in July 2012 with searches of the PubMed database. The most recent literature update was performed through March 26, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Inherited thrombophilias are a group of disorders that predispose individuals to thrombosis. Genetic testing is available for some of these disorders and could assist in the diagnosis and/or management of patients with thrombosis. For example, testing is available for types of inherited thrombophilia, including variants in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, the factor V gene (factor V Leiden [FVL] variant), and the prothrombin (factor II) gene.

Population Reference No. 1 

MTHFR Variant Testing

Clinical Context and Test Purpose

The purpose of genetic testing for variants in the MTHFR gene is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical management without testing, in patients who are asymptomatic with or without a personal or family history of venous thromboembolism (VTE).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are asymptomatic with or without a personal or family history of VTE.

Interventions

The test being considered is genetic testing for variants in MTHFR.

Patients who are asymptomatic with or without a personal or family history of VTE are actively managed by cardiologists and primary care providers in an outpatient clinical setting.

Comparators

Comparators of interest include standard clinical management without testing.

Outcomes

The general outcomes of interest are morbid events and treatment-related morbidity.

The beneficial outcomes of a true-positive test result are an appropriate treatment for VTE. The beneficial outcome of a true-negative test result is potentially avoiding unnecessary treatment.

The harmful outcome of a false-positive result is having unnecessary treatment for VTE. The harmful outcome of a false-negative result is a potential delay in diagnosis and treatment.

Table 2. Outcomes of interest for individuals who are asymptomatic with or without a personal or family history of venous thromboembolism

VTE: venous thromboembolism

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

• The study population represents the population of interest. Eligibility and selection are described.

• The test is compared with a credible reference standard.

• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operating characteristic, area under receiver operating characteristic, c-statistic, likelihood ratios) may be included but are less informative.

• Studies should also report reclassification of diagnostic or risk category.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Variants in the MTHFR gene are associated with hyperhomocysteinemia, which in turn is considered a weak risk factor for VTE.^5,

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

The clinical utility of testing for homocysteine levels has not been established. There is a large body of literature on the association between homocysteine levels and coronary artery disease, and clinical trials have assessed the impact of lowering homocysteine levels. This body of evidence has indicated that testing or treating for homocysteinemia is not associated with improved outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The evidence for the association between MTHFR and VTE is not definitive. Some studies have shown an association,^5,6,7,8,9, while others have not.^10,11,12, One larger study (N=9231), the 2007 MEGA study, reported by Bezemer et al (2007), showed no association between the common MTHFR 677C>T variant with recurrent VTE.^10, An RCT by der Heijer et al (2007) reported no reduction in VTE associated with the treatment of hyperhomocysteinemia.^13,

Gao et al (2020) evaluated the association between the MTHFR C677T and MTHFR A1298C polymorphisms and the risk of VTE in a meta-analysis of 32 case-control studies.^14, Pooled results demonstrated an increased susceptibility to VTE with MTHFR C677T homozygotes (odds ratio [OR]=0.73; 95% confidence interval [CI], 0.60 to 0.89) and MTHFR C677T homozygotes/heterozygotes (OR=0.80; 95% CI, 0.71 to 0.90) compared to those without a mutation. When results were stratified by ethnicity, a significant association was maintained in the Asian population, but results were not significant for the White population. For the MTHFR A1298C polymorphism, there was no significant association between homozygotes (OR=0.90; 95% CI 0.66 to 1.23) or homozygotes/heterozygotes (OR=0.95; 95% CI, 0.83 to 1.07) compared to those without a mutation for susceptibility to VTE.

Section Summary: MTHFR Variant Testing

Published evidence on the utility of testing for MTHFR variants in patients who have or are at risk for VTE is limited. Given the available evidence, and lack of clinical utility for serum homocysteine testing in general, it is unlikely that testing for MTHFR will improve outcomes.

Population Reference No. 2 

Factor V Leiden and Prothrombin Variant Testing

Clinical Context and Test Purpose

The purpose of genetic testing for variants in coagulation factor V and coagulation factor II is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical management without testing, in individuals who are asymptomatic with or without a personal or family history of VTE.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are asymptomatic with or without a personal or family history of VTE.

Interventions

The test being considered is genetic testing for variants in coagulation factor V and coagulation factor II.

Comparators

Comparators of interest include standard clinical management without testing.

Outcomes

The general outcomes of interest are morbid events and treatment-related morbidity (Table 3).

The beneficial outcomes of a true-positive test result are an appropriate treatment for VTE. The beneficial outcome of a true-negative test result is potentially avoiding unnecessary treatment.

The harmful outcome of a false-positive result is having unnecessary treatment for VTE. The harmful outcome of a false-negative result is a potential delay in diagnosis and treatment.

Table 3. Outcomes of interest for individuals who are asymptomatic with or without a personal or family history of venous thromboembolism

VTE: Venous thromboembolism

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

• The study population represents the population of interest. Eligibility and selection are described.

• The test is compared with a credible reference standard.

• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operating characteristic, area under receiver operating characteristic, c-statistic, likelihood ratios) may be included but are less informative.

• Studies should also report reclassification of diagnostic or risk category.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The clinical validity and clinical utility are discussed for 3 distinct patient populations. They are:

• Individuals without a personal history of VTE

• Individuals with a personal history of VTE

• Family members of individuals with thrombophilia

Review of Evidence

Individuals Without a Personal History of Venous Thromboembolism

Factor V Leiden Variant

Individuals with FVL or prothrombin variants have an elevated risk of thrombosis compared with the general population. For individuals with the FVL variant, the risk may be 2- to 5-fold higher than that in the general population. In a retrospective study by Middledorp et al (1998) of first-degree relatives of individuals with documented VTE and heterozygosity for FVL, those with an FVL variant had an absolute annual risk for a first VTE episode of 0.45%, compared with an annual incidence of 0.1% in those family members without the variant.^15,

Prothrombin G20210A Variant

For the prothrombin G20210A variant, risk also has been estimated to be 2 to 5 times greater than the general population.^16, A meta-analysis by Gohil et al (2009) evaluated 79 studies and reported a combined relative risk of 3.0.^17, Heterozygosity for the prothrombin G20210A variant also is associated with an increased risk of upper-extremity thrombosis, estimated to be 5 times that of the general population.^16,

Individuals With a Personal History of Venous Thromboembolism

Factor V Leiden Variant

An Agency for Healthcare Research and Quality (AHRQ) report by Segal et al (2009) reviewed the evidence on recurrence risk for patients with a history of VTE and the FVL variant.^18, For individuals with a heterozygous FVL variant, 13 studies compared recurrence risk to a variant with recurrence risk without a variant. Pooled analysis of these 13 studies yielded an OR of 1.56 (95% CI, 1.14 to 2.12) for recurrent VTE in patients with the FVL variant. For patients with a homozygous variant, 7 studies evaluated recurrence risk. Pooled odds for recurrent VTE in these studies was 2.65 (95% CI, 1.18 to 5.97).

Not all studies have reported an increased risk of recurrent VTE in patients with inherited thrombophilia. For example, the 2005 Leiden Thrombophilia Study followed 474 patients who had completed a course of anticoagulation for a mean of 7.3 years.^19, All patients were tested for thrombophilia at baseline, with 20% found to have an FVL variant and 6% a prothrombin variant. Recurrence did not increase either for patients with an FVL variant or patients with a prothrombin variant. For FVL, there was a mild increase in recurrence risk that was not statistically significant on multivariate analysis (hazard ratio [HR], 1.3; 95% CI, 0.8 to 2.1).

One of the larger RCTs that was included in the above-mentioned AHRQ review was the 2008 influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin trial. This trial randomized 738 patients from 16 clinical centers to low-intensity or conventional-intensity anticoagulation.^20, All patients were tested for inherited thrombophilias, and recurrence risk was calculated for patients with and without inherited thrombophilia. For patients with an FVL variant, there was no increased risk of recurrence over a mean follow-up of 2.3 years (HR=0.7; 95% CI, 0.2 to 2.6).

Prothrombin G20210A Variant

The AHRQ report by Segal et al (2009) identified 18 studies that evaluated recurrence risk in patients heterozygous for the prothrombin G20210A variant.^18, Some of these studies included only heterozygotes, while others combined both heterozygotes and homozygotes. For 9 studies that included only heterozygotes, pooled odds for recurrent VTE was 1.45 (95% CI, 0.96 to 2.2). For 7 studies that did not specify homozygous or heterozygous, the combined odds were 0.73 (95% CI, 0.37 to 1.44).

The prothrombin G20210A variant is less common and, therefore, the number of patients evaluated in clinical trials and cohort studies is smaller than for FVL. In the 2008 influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin trial, the risk of recurrent VTE in those with the prothrombin G20210A variant could not be calculated because there were no recurrences among 60 patients with the variant.^20, In the 2005 Leiden Thrombophilia Study, 29 patients had a prothrombin variant.^19, For patients with a prothrombin variant, there was no increased risk of recurrence (HR=0.7; 95% CI, 0.3 to 2.0). Factors that predicted recurrence were mainly clinical variables, such as provoked versus unprovoked VTE, patient sex, and oral contraceptive use.

Family Members of Individuals with Thrombophilia

Factor V Leiden

The AHRQ (2009) report identified 9 studies that evaluated VTE risk in family members of a proband with a heterozygous variant. The pooled odds for future VTE was 3.49 (95% CI, 2.46 to 4.96). Six studies evaluated a total of 48 probands with homozygous FVL variants. The pooled odds for family members of homozygous individuals was 18 (95% CI, 7.8 to 40).

In a larger study of VTE risk in family members, Lijfering et al (2009) pooled results from 5 retrospective family studies of thrombophilia.^21, A total of 2479 relatives of patients with thrombophilia who were themselves also tested for thrombophilia were included. For relatives with FVL variants, the annual incidence of thrombosis was 0.49% (95% CI, 0.39% to 0.60%). In relatives without thrombophilia, the incidence of VTE was approximately 0.05% per year, and the adjusted relative risk for VTE in relatives with an FVL variant was 7.5 (95% CI, 4.4 to 12.6). In patients treated with anticoagulation, the annual risk of major bleeding was 0.29% (95% CI, 0.03% to 1.04%).

Prothrombin Variants

Evidence on VTE risk for family members of individuals with a prothrombin variant is lower than for FVL, with 5 studies identified by Segal et al (2009) in the AHRQ report evaluating heterozygotes and only 1 study evaluating homozygotes.^18, For heterozygote probands, family members had an odds for future VTE of 1.89 (95% CI, 0.35 to 10.2).

In the Lijfering et al (2009) family study, relatives with prothrombin variants had an annual VTE incidence of 0.34% (95% CI, 0.22% to 0.49%).^21, In relatives without thrombophilia, the incidence of VTE was approximately 0.05% per year, and the adjusted relative risk for VTE in relatives with a prothrombin variant was 5.2 (95% CI, 2.8 to 9.7).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

The clinical utility of genetic testing for thrombophilia is considered in the context of overall VTE risk and the risk-benefit ratio of treatment, primarily with anticoagulants. The following factors are part of the decision-making process on whether to test for:

• 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 the benefit in patients with a relatively low absolute risk of thrombosis.

Some have suggested that functional testing for activated protein C resistance may be more clinically relevant than genetic testing for FVL in persons with an increased risk of thromboembolism.^22,

Individuals Without a Personal History of Venous Thromboembolism

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No published studies identified have directly evaluated the clinical utility of screening asymptomatic individuals for inherited thrombophilia.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

It is unlikely that screening asymptomatic individuals will result in a net health benefit because prophylactic anticoagulation is likely to do more harm than benefit. Risk of major bleeding with full anticoagulation is approximately 1% per year; therefore, the number of major bleeding episodes may far exceed the number of VTEs prevented. Knowledge of thrombophilia status may lead to behaviors that reduce VTE risk, such as avoidance of prolonged immobility, but this is unproven.

Individuals With a Personal History of Venous Thromboembolism

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Case-Control Studies

The 2008 MEGA study was a large, population-based, case-control study that evaluated whether testing for thrombophilia in patients with the first episode of VTE was associated with a decrease in recurrence rate.^23, The MEGA database was comprised of 5051 patients between the ages of 18 and 70 years with their first episode of VTE. Researchers identified 197 patients with a recurrence of VTE and matched these patients by age, sex, year of VTE, and geographic region with 324 patients who were free of recurrent VTE. Recurrence rates for VTE were similar in patients tested for thrombophilia compared with patients not tested (OR=1.2; 95% CI, 0.9 to 1.8). The presence of FVL or the prothrombin G20210A variant was not associated with an increased recurrence rate (OR=0.8; 95% CI, 0.3 to 2.6).

Cohort Studies

Mahajerin et al (2014) conducted a single-center, retrospective cohort study of pediatric patients (mostly adolescents) who presented with VTE (88% deep vein thrombosis) “to help clarify the role of thrombophilia testing in pediatric VTE.”^24, Of 392 inpatients and outpatients, thrombophilia tests (FVL; prothrombin gene variant; MTHFR; protein C, protein S, and antithrombin activity; antiphospholipid antibodies; plasminogen activator inhibitor-1 levels and variant testing) were ordered in 310 (79%) patients. Of these, testing found 37 positive (12%) results. Given that most patients had at least 1 risk factor for VTE and, as noted by the authors, the “presence or absence of thrombophilia rarely influences VTE management,” this evidence does not support thrombophilia genetic testing in pediatric patients who present with VTE.

Cross-Sectional Studies

A study by Hindorff et al (2009) surveyed 112 primary care physicians about the impact of FVL testing in patients with VTE.^25, Most physicians indicated that they would use results in clinical practice, with 82% reporting that they would use results to counsel patients on risk of recurrence and 67% reporting that they would use results to make treatment changes. However, physician confidence in their decisions was not high, including decisions to order FVL testing.

Family Members of Individuals with Thrombophilia

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are no comparative trials assessing testing with no testing in relatives of individuals who have thrombophilia.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The clinical utility of testing depends on the balance between the benefit of altering management as a result of knowledge of variant status and the risk of bleeding with the intensification of anticoagulation. This risk-benefit is unknown, as previously discussed. The absolute risk of VTE remains low, even in patients with inherited thrombophilia, and potential risks of prophylactic treatment with anticoagulants may outweigh potential benefits.

Section Summary: Factor V Leiden and Prothrombin Variant Testing

The clinical validity of genetic testing for thrombophilia has been evaluated by assessing the association between thrombophilia status and VTE in various clinical populations. For populations discussed herein, the clinical validity has been reported in numerous case-control and cohort studies. The presence of an FVL or a prothrombin gene variant is associated with an increased risk for subsequent VTE across a number of populations. However, the magnitude of the association is relatively modest, with ORs most commonly between 1 and 2, except for family members of individuals with inherited thrombophilia, for whom an OR is somewhat higher.

The clinical utility of testing for FVL or prothrombin variants has not been demonstrated. Although the presence of inherited thrombophilia increases the risk for subsequent VTE events, the increase is modest, and the absolute risk of thrombosis remains low. Available prophylactic treatments, such as anticoagulation, have defined the risks of major bleeding and other adverse events that may outweigh the reduction in VTE and therefore result in net harm. Currently, available evidence has not defined a role for thrombophilia testing in decisions concerning the initiation of prophylactic anticoagulation or the length of anticoagulation treatment.

Population Reference No. 3 

Pregnancy and Other High-Risk Conditions

Clinical Context and Test Purpose

The purpose of genetic testing for variants in coagulation factor V and coagulation factor II is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical management without testing, in individuals who are asymptomatic with increased VTE risk (eg, due to pregnancy).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are asymptomatic with increased VTE risk (eg, due to pregnancy).

Interventions

The test being considered is genetic testing for variants in coagulation FVL and coagulation factor II.

Comparators

Comparators of interest include standard clinical management without testing.

Outcomes

The general outcomes of interest are morbid events and treatment-related morbidity (Table 4).

Table 4. Outcomes of interest for individuals who are asymptomatic with increased venous thromboembolism risk (eg, due to pregnancy)

VTE: Venous thromboembolism

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

• The study population represents the population of interest. Eligibility and selection are described.

• The test is compared with a credible reference standard.

• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operating characteristic, area under receiver operating characteristic, c-statistic, likelihood ratios) may be included but are less informative.

• Studies should also report reclassification of diagnostic or risk category.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Pregnancy

Evidence of the risk of recurrent pregnancy loss in women with FVL or a prothrombin gene variant comprises primarily retrospective case-control and cohort studies. Several case-control studies have reported a higher prevalence of FVL in women with recurrent, unexplained pregnancy loss compared with controls (OR range, 2 to 5).^26, Retrospective cohort studies have found a 2- to 3-fold increased risk of pregnancy loss in FVL heterozygous carriers; homozygotes have a 2-fold higher risk than heterozygous carriers. Risk of pregnancy loss for heterozygous carriers is highest during the second and third trimesters.

A systematic review by Bradley et al (2012) analyzed evidence on the association between FVL and prothrombin variants with pregnancy loss.^27, They 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 noncarriers. Four cohort studies met all 4 criteria; these studies primarily included patients with FVL variants. Two of the 4 studies reported a significantly increased rate of recurrence for carriers and 2 did not. Pooled analysis of these 4 studies yielded significantly increased odds for recurrent pregnancy loss in carriers (OR=1.93; 95% CI, 1.21 to 3.09).

A systematic review by Liu et al (2021) evaluated the association between hereditary thrombophilias, including FVL and prothrombin G20210A, and recurrent pregnancy loss.^28, Observational studies were included if they compared at least 2 groups of patients - 1 with hereditary thrombophilia and 1 without hereditary thrombophilia. There were 89 studies included in the analysis, with 81 evaluating the risk of FVL and 64 evaluating the risk of prothrombin G20210A on recurrent pregnancy loss. Pooled analysis of FVL demonstrated an increased risk for recurrent pregnancy loss with the variant (OR=2.44; 95% CI, 1.96 to 3.03). Pooled analysis for prothrombin G20210A also demonstrated an increased risk for recurrent pregnancy loss with the variant (OR=2.08; 95% CI, 1.61 to 2.68). Both analyses were limited by high heterogeneity across the included studies.

A number of other meta-analyses have concluded that the risk of pregnancy loss for patients who are heterozygous for the prothrombin G20210A variant also is increased, in the 2- to 3-fold range.^16,

Oral Contraceptives

Oral contraceptive use alone is associated with an approximately 4-fold increase in the risk of thrombosis; in combination with FVL, risk multiplies 34-fold in heterozygotes and more than 100-fold in homozygotes. However, the absolute incidence estimated in a study by Vanderbroucke et al (1994) was 28 thrombotic events per 10,000 per year, 2% of which were estimated to be fatal.^29,

Hormone Replacement Therapy

Women using hormone replacement therapy have a 2- to 4-fold increased risk of thrombosis.^26, Absolute risk is low and may be restricted to the first year of use. Limited data have suggested that women using selective estrogen receptor modulators (eg, tamoxifen) may have a similarly increased risk.^26,

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No studies have directly evaluated the clinical utility of thrombophilia testing in pregnant women.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

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.^30,31, 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.^27,32,33, In contrast, the real risks of anticoagulation include bleeding, thrombocytopenia, and allergic reactions. There also are costs and inconveniences associated with these treatments.

Bradley et al (2012) 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.^27, 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, MTHFR 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 increased odds of stillbirth for maternal homozygous FVL variant (2/488 [0.4%] versus 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.^34,

An open-label, international, multicenter randomized trial, reported by Rodger et al (2014), evaluated antepartum use of the low-molecular-weight heparin, dalteparin, in women with the prothrombin variant.^35, 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.

The current chapter (updated in 2021) on prothrombin-related thrombophilia in GeneReviews concluded: “Once the F2 20210G>A variant has been identified in a family member, prenatal testing for a pregnancy at increased risk for prothrombin thrombophilia and preimplantation genetic testing is possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider the use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ”^16,

Section Summary: Pregnancy and Other High-Risk Conditions

Evidence of the risk of recurrent pregnancy loss in women with FVL or a prothrombin gene variant comprises primarily retrospective case-control and cohort studies. No studies have directly evaluated the clinical utility of thrombophilia testing in pregnant women, and the clinical utility of testing for FVL or prothrombin variants in pregnant women has not been demonstrated.

Summary of Evidence

For individuals who are asymptomatic with or without a personal or family history of VTE or who are asymptomatic with increased VTE risk (eg, due to pregnancy) who receive genetic testing for variants in MTHFR, or genetic testing for coagulation factor V and coagulation factor II, the evidence includes a large RCT, prospective cohort analyses, retrospective family studies, case-control studies, and meta-analyses. Relevant outcomes are morbid events and treatment-related morbidity. The clinical validity of genetic testing has been demonstrated by the presence of a FVL 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 ORs most commonly between 1 and 2 , except for family members of individuals with inherited thrombophilia, for whom ORs are somewhat higher. The clinical utility of testing for FVL or prothrombin variants has not been demonstrated. Although the presence of inherited thrombophilia increases the risk for subsequent VTE events, the increase is modest, and the absolute risk of thrombosis remains low. Available prophylactic treatments (eg, anticoagulation) have defined risks of major bleeding and other adverse events that may outweigh the reduction in VTE and therefore result in net harm. Currently, available evidence has not defined a role for thrombophilia testing for decisions on initiation of prophylactic anticoagulation or the length of anticoagulation treatment. For MTHFR testing, clinical validity and clinical utility of genetic testing are uncertain. Because clinical utility of testing for elevated serum homocysteine itself has not been established, the utility of genetic testing also has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input from Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input

In response to requests, input was received from 4 physician specialty societies (6 reviewers) and 6 academic medical centers, for a total of 12 reviewers, while this policy was under review in 2012. Input was mixed, and there was no consensus that genetic testing for thrombophilia was medically necessary for any of the specific clinical situations included. Several reviewers noted that testing could be useful in isolated instances but were unable to define specific criteria for testing.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Many guidelines and position statements on testing for thrombophilia have been published over the last 2 decades. These guidelines have evolved over time, are often inconsistent, and do not typically give specific parameters on when to perform genetic testing. The following are examples of U.S. guidelines developed by major specialty societies and published more recently.

American Board of Internal Medicine Foundation- Choosing Wisely Campaign

Choosing Wisely, an initiative of the American Board of Internal Medicine Foundation, seeks to promote discussions between clinicians and patients to choose care that is: supported by evidence, not duplicative of other tests or procedures already received, free from harm, and truly necessary. Medical specialty societies and their national organizations have identified tests or procedures commonly used in their field whose necessity should be questioned and discussed. The following medical specialist groups have contributed recommendations to Choosing Wisely lists specifically related to testing for inherited thrombophilias (Table 5).

Table 5. Medical Society Recommendations on Testing for Inherited Thrombophilias

Abbreviations: NA: not available.

American College of Chest Physicians

Since 2016, the American College of Chest Physicians (2021) guidelines and expert panel report on antithrombotic therapy for venous thromboembolism (VTE) disease no longer include recommendations for pregnant women with known factor V Leiden or prothrombin G20210A variants, which had been included in the 2012 edition.^39,40,41,Also, there are no guidelines on genetic testing for thrombophilia. The 2008 edition had indicated that the presence of a hereditary thrombophilia was not a major factor to guide duration of anticoagulation for VTE.^42,

American College of Medical Genetics and Genomics

In 2018, the American College of Medical Genetics and Genomics (ACMG) published updated technical standards for genetic testing for variants associated with VTE, with a focus on factor V Leiden and factor II.^43, The standards do not make recommendations on the indications for testing, and the authors note that testing indications from different professional organizations vary, referring to a review of professional society guidelines published by De Stefano et al (2013).^44,

American College of Obstetricians and Gynecologists

The American College of Obstetricians and Gynecologists (2018; reaffirmed in 2022) published management guidelines for inherited thrombophilias in pregnancy.^45, These guidelines stated that a definitive causal link between inherited thrombophilias and adverse pregnancy outcomes could not be made. Screening for inherited thrombophilias is controversial, but may be considered for pregnant women in the following situations if testing will influence management:

• A personal history of VTE, with or without a recurrent risk factor, and no prior thrombophilia testing.

• A first-degree relative (eg, parent, sibling) with a history of high-risk thrombophilia.

Table 6. Guidelines for Managing Inherited Thrombophilias During Pregnancy

FVL: factor V Leiden; GOE: grade of evidence; LOE: level of evidence; VTE: venous thromboembolism.

Anticoagulation Forum

In 2016, Stevens et al. published a guidance document initiated by the Anticoagulation Forum.^46, The guidance was intended to inform clinical decisions regarding duration of anticoagulation following VTE and primary prevention of VTE in relatives of affected patients. Statements were based on existing guidelines and consensus expert opinion when guidelines were lacking. The authors concluded that, "Thrombophilia testing is performed far more frequently than can be justified based on available evidence; the majority of such testing is not of benefit to the patient and may be harmful." Table 7 summarizes the guidance statements for each question considered in the document.

Table 7. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia (adapted from Stevens et al [2016])

VTE: Venous thromboembolism.

Evaluation of Genomic Applications in Practice and Prevention

The Evaluation of Genomic Applications in Practice and Prevention (2011) recommendations did not support the clinical utility of genetic testing for factor V Leiden and prothrombin variants for prevention of initial episodes of VTE or for recurrence.^47, The recommendations have been archived.

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT: national clinical trial.

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Codes

Applicable Modifiers

N/A

Policy History