Genetic Testing for Inherited Thrombophilia

POLICY NUMBER

A.2.04.82

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 variant), and the prothrombin (factor II) gene.

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%. 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. 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 one 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 (SLE) and/or other rheumatologic disorders

• Myeloproliferative disorders

• Liver dysfunction

• Nephrotic syndrome

• Hereditary factors.

Pregnancy is often considered a special circumstance because of its frequency and the unique considerations for preventing and treating VTE. Pregnant women experience 10 to 14 VTE events per 10,000 deliveries. Furthermore, approximately half of all pregnancy-associated VTEs occur postpartum, most within 6 weeks after delivery. Compared to similarly aged nonpregnant controls, the daily risk of VTE during pregnancy and postpartum is 3 to 10 times higher and 12 to 35 times higher, respectively. Additionally, up to a quarter of pregnancy-associated VTEs are recurrent events.

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 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-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. 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. In a 2024 systematic review and meta-analysis of 107 studies (N=107,130), VTE risk in adults with hereditary thrombophilia was highest in homozygous FVL (odds ratio [OR], 5.58; 95% CI, 4.61 to 6.74) and homozygous prothrombin G20210A (OR, 5.16; 95% CI, 3.12 to 8.52).

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 in this policy 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 high-risk for thrombosis (e.g. pregnancy, planned major surgery, or exogenous hormone use).

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) 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 LDTs 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.

Several genetic tests for thrombophilia have been cleared for marketing by the FDA through the 510(k) process for use as an aid in the diagnosis of patients with suspected thrombophilia. Some of these tests are listed below.

Genetic Tests for Thrombophilia Cleared by the 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).

Related medical policies are –

POLICY

Genetic testing for inherited thrombophilia, including testing for the factor V Leiden variant, prothrombin gene variants, and variants in the MTHFR gene, is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetics Nomenclature Update

The Human Genome Variation Society (HGVS) 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 1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization (HUGO), and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) 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 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

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.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

11/15/2012: Approved by Medical Policy Advisory Committee.

11/06/2013: Policy reviewed; no changes.

09/02/2014: Policy reviewed; description updated. Policy statement unchanged.

07/30/2015: Code Reference section updated for ICD-10.

11/03/2015: Policy description updated regarding genetic tests. Policy statement unchanged. Investigative definition updated in the policy guidelines section.

06/07/2016: Policy number A.2.04.82 added.

06/20/2017: Policy description updated regarding genetic tests for thrombophilia. Policy statement updated to change "mutation" to "variant." Policy Guidelines updated to add standard terminology for variant classification and to add genetic counseling information.

06/12/2018: Policy description updated regarding genetic tests. Policy statement unchanged. Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

06/06/2019: Policy description updated. Policy statement unchanged.

06/18/2020: Policy description updated regarding testing. Policy statement unchanged.

08/02/2021: Policy description updated regarding inherited thrombophilia and tests. Medical policy link updated. Policy statement unchanged.

06/17/2022: Policy description updated regarding genetic tests for thrombophilia. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.

07/13/2023: Policy description updated regarding genetic tests for thrombophilia. Policy statement unchanged. Policy Guidelines updated to change "patients" to "individuals."

06/12/2024: Policy description updated regarding venous thromboembolism. Policy statement unchanged.

12/19/2024: Code Reference section updated to add new CPT code 0529U effective 01/01/2025.

08/12/2025: Policy description updated regarding venous thromboembolism in pregnancy and hereditary thrombophilia. Policy statement unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.82

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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