Genetic Testing for Hereditary Thrombophilia Product Applicability

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Medical Policy

Genetic Testing for Hereditary Thrombophilia

Policy Number: OCA 3.728 Version Number: 11 Version Effective Date: 03/01/21

Product Applicability All Plan+ Products

Well Sense Health Plan Boston Medical Center HealthNet Plan Well Sense Health Plan MassHealth Qualified Health Plans/ConnectorCare/Employer Choice Direct Senior Care Options ◊

Notes: + Disclaimer and audit information is located at the end of this document. ◊ The guidelines included in this Plan policy are applicable to members enrolled in Senior Care Options only if there are no criteria established for the specified service in a Centers for Medicare & Medicaid Services (CMS) national coverage determination (NCD) or local coverage determination (LCD) on the date of the prior authorization request. Review the member’s product-specific benefit documents at www.SeniorsGetMore.org to determine coverage guidelines for Senior Care Options.

Policy Summary The Plan considers targeted genetic testing for factor V Leiden (factor V/F5) and prothrombin (factor II/F2) gene mutations associated with hereditary thrombophilia to be medically necessary to identify predisposition to thrombosis when Plan criteria are met. Testing for variants in the methylenetetrahydrofolate reductase (MTHFR) C677T gene is considered experimental and investigational. Prior authorization is required. The Plan’s prior authorization requirements for genetic testing are based on the type of genetic test requested, indication(s) for testing, and if the test is ordered, administered, and processed by participating providers and participating laboratories (or non- participating providers and non-participating laboratories).

Genetic Testing for Hereditary Thrombophilia

+ Plan refers to Boston Medical Center Health Plan, Inc. and its affiliates and subsidiaries offering health coverage plans to enrolled members. The Plan operates in Massachusetts under the trade name Boston Medical Center HealthNet Plan and in other states under the trade name Well Sense Health Plan. 1 of 29

For genetic tests ordered, administered, and processed by participating providers and participating laboratories, Plan prior authorization is required for all molecular and chromosomal genetic testing EXCEPT for prenatal genetic screening tests for a member with one (1) of the primary pregnancy diagnosis codes specified in the Applicable Coding section of the following medical policies: Genetic/Genomic Testing and Pharmacogenetics medical policy, policy number OCA 3.7272; Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573; and/or Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571. The primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. When genetic tests are order, administered, and processed by non-participating providers and/or non- participating laboratories (NOT contracted with the Plan), prior authorization is required for all genetic testing, including prenatal genetic screening tests; the list of primary diagnosis codes waived from the prior authorization process would NOT apply to non-participating providers and non-participating laboratories. Biochemical genetic tests used to study the amount or activity level of proteins to indicate changes to the DNA require prior authorization when specified in the Plan’s Code Look-Up Tools, Prior Authorization Matrix, or a Plan medical policy available at www.bmchp.org for services provided to BMC HealthNet Plan members and at www.wellsense.org for Well Sense Health Plan members.

The Plan recommends that adequate pre-test genetic counseling and post-test genetic counseling be provided by a health care professional with expertise in genetics for all genetic testing conducted with Plan members. Genetic counseling provided to a Plan member (and/or guardian if the member is under the age of 18) should be documented in the member’s medical record and conducted by an appropriately trained practitioner with expertise and experience in genetics, including a provider acting within the scope of his/her license and practice, clinical geneticist, or genetic counselor.

The Plan complies with coverage guidelines for all applicable state-mandated benefits and federally- mandated benefits that are medically necessary for the member’s condition. It will be determined during the prior authorization process if the genetic test is considered medically necessary or experimental and investigational for the requested indication. The Plan’s Medically Necessary medical policy, policy number OCA 3.14, indicates the product-specific definitions of medically necessary treatment, and the Plan’s Experimental and Investigational Treatment medical policy, policy number OCA 3.12, includes the product-specific definitions of experimental or investigational treatment. Plan- adopted InterQual® criteria and the following medical policies include additional prior authorization guidelines for genetic testing and related services:

1. Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, with the medical policy listing the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization; applicable InterQual® criteria are used to determine medical necessity

Genetic Testing for Hereditary Thrombophilia

2. Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances medical policy, policy number OCA 3.98, includes guidelines related to specimen validity testing using DNA authentication in conjunction with drug testing for BMC HealthNet Plan members

3. Genetic/Genomic Testing and Pharmacogenetics medical policy, policy number OCA 3.727, with either medical policy criteria or Plan-adopted InterQual® criteria used to determined medical necessity based on the type of genetic test requested and the indication(s) for testing; the medical policy lists the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization

4. Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571, with the medical policy listing the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization; applicable InterQual® criteria are used to determine medical necessity

5. Preimplantation Genetic Testing medical policy, policy number OCA 3.726, with medical policy criteria used to determine medical necessity ONLY when preimplantation genetic testing is a covered service for a Plan member

Description of Item or Service Molecular Genetic Testing for Hereditary Thrombophilia: Molecular genetic tests that identify genetic variant defects associated with a predisposition to thrombosis. A genetic susceptibility to thrombosis in combination with other risk factors increases the individual’s risk of venous thromboembolism (VTE). Genetic testing for gene variants associated with thrombophilias include testing of factor V Leiden, prothrombin gene G20210A, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene. See the Medical Policy Statement section and the Limitations section of this policy for Plan criteria and prior authorization guidelines for these tests. Guidelines for factor V Leiden and prothrombin gene G20210A testing to determine predisposition to thrombosis are outlined in the Medical Policy Statement section. Criteria for methylenetetrahydrofolate reductase (MTHFR) C677T genetic testing to diagnose hereditary thrombophilia are specified in the Limitations section of this Plan policy.

Thrombophilia Panel: In addition to the molecular genetic tests specified above, a thrombophilia panel may include the following biochemical genetic tests, coagulation tests, and antibody screening tests (that do NOT require Plan prior authorization).

1. Protein C activity level

2. Protein S activity level

3. Antithrombin III activity (recommended for recurrent VTE)

Genetic Testing for Hereditary Thrombophilia

4. Antiphospholipid antibody screening (including Lupus anticoagulant, anticardiolipin antibodies, and beta 2 glycoprotein antibodies) to rule out acquired thrombophilia

In selected high risk obstetric or VTE patients or those with a striking family history of thrombosis, additional testing under the direction of a hematologist, perinatologist or clinical geneticist may be indicated.

Medical Policy Statement Targeted genetic testing for factor V Leiden (factor V/F5) and prothrombin (factor II/F2) gene mutations associated with inherited thrombophilia is considered medically necessary when ALL of the following applicable Plan criteria are met and documented in the member’s medical record, as specified below in items 1 through 3:

1. The result of the testing will directly impact the treatment being delivered to the member; AND

2. Member has at least ONE (1) of the following medical conditions, as specified below in item a or item b:

a. Member has at least ONE (1) of the following obstetric complications (or a history of any of the following obstetric complications), as listed below in items (1) through (6):

(1) Recurrent pregnancy loss (i.e., two [2] or more lost pregnancies); OR

(2) Early onset preeclampsia; OR

(3) Placental abruption; OR

(4) Severe intrauterine growth restriction (IUGR); OR

(5) Placental abnormality related to vascular underperfusion; OR

(6) Perinatal arterial ischemic stroke (and would include testing for maternal and infant thrombophilias and cerebral venous sinus thrombosis/cerebral sinovenous thrombosis); OR

b. Member has a personal history of single or multiple venous thromboembolism (VTE) of unknown etiology and at least ONE (1) of the following criteria is met, as specified below as item (1) or item (2):

(1) Member has had a VTE of unknown etiology before age 50 (with or without a family history of known thrombophilia or thrombosis, i.e., VTE or pulmonary embolism); OR

Genetic Testing for Hereditary Thrombophilia

(2) Member has had a VTE of unknown etiology (at any age) and meets at least ONE (1) of the following criteria, as specified below in item (a) or item (b):

(a) Member has at least ONE (1) first-degree relative with a documented genetic thrombophilia diagnosis; OR

(b) Member has at least ONE (1) first-degree relative with a history of thrombosis (VTE or pulmonary embolism) of presumed unknown etiology before age 50; AND

3. ONE (1) or more of the following types of molecular genetic testing will be conducted (and does REQUIRE Plan prior authorization), as specified below in item a and/or item b:

a. Factor V Leiden (FVL) variant analysis in the factor V (F5) gene (p.Arg534Gln, R534Q, F5 c. 1601G>A); AND/OR

b. Prothrombin/factor II (F2) gene 20210G>A (G20210A) variant analysis

Limitations

1. Plan Medical Director review is required for individual consideration when genetic testing for hereditary thrombophilia is requested to aid in the diagnosis and treatment of pediatric ischemic stroke, with supporting medical record documentation demonstrating that there is no alternative explanation for the stroke.

2. Genetic testing for hereditary thrombophilia requires Plan Medical Director review when the treating provider recommends testing and the Plan’s medical necessity criteria specified in the Medical Policy Statement section are NOT met, including but not limited to testing for the following indications: venous thrombosis in unusual sites (e.g., hepatic, mesenteric, and cerebral veins), warfarin-induced skin necrosis, or is an infant with neonatal purpura fulminans.

3. Genetic testing for hereditary thrombophilia is considered either NOT medically necessary or experimental and investigational when applicable Plan criteria specified in the Medical Policy Statement section of this policy are NOT met. Prior authorization requests that do NOT meet Plan criteria require Plan Medical Director review and approval, including but not limited to ANY of the following conditions/indications, as specified below in items a through f:

a. Testing of a member when the indication for testing (venous thrombosis) is related to pregnancy or the prescribing of oral contraceptives (including testing as a screening test before ordering oral contraceptives) when applicable medical necessity criteria in the Medical Policy Statement section are NOT met; OR

Genetic Testing for Hereditary Thrombophilia

b. Testing for a member less than age 50 years of age (on the date of service) with the first incident of venous thrombosis with a known etiology unrelated to thrombophilia, and the member has no history of a first degree relative with thrombosis;ǂ OR

ǂ Note: Examples of etiologies associated with venous thrombosis that are unrelated to hereditary thrombophilia may include trauma or cancer. Studies have shown that moderate or heavy smoking may increase a patient’s risk of venous thrombosis when present in conjunction with other established risk factors for venous thrombosis such as a personal history of myocardial infarction or cancer.

c. Testing for a member age 50 years of age or older (on the date of service) with the first incident of venous thrombosis with a known etiology unrelated to thrombophilia, and the member has no family history of recurrent venous thrombosis and no history of a first degree relative with thrombosis;ǂ OR

d. Testing for an asymptomatic member with or without a family history of recurrent VTE; OR

e. Testing of a member when the indication is related to hormonal replacement therapy (and Plan criteria are not met); OR

f. General population screening.

4. Genetic testing of methylenetetrahydrofolate reductase (MTHFR) to diagnose hereditary thrombophilia is considered experimental and investigational.¥

¥ Note: Review applicable InterQual® criteria (or the Plan’s Genetic/Genomic Testing and Pharmacogenetics medical policy, policy number OCA 3.727, when applicable InterQual® criteria are not available) for the Plan’s medical necessity guidelines for MTHFR genetic testing when not related to the diagnosis of hereditary thrombophilia (e.g., MTHFR genotyping used to screen for known, rare MTHFR variants in relatively closed or isolated populations at high risk, to detect rare variants in prenatal screening where the condition has already been diagnosed in a family, and/or MTHFR pharmacogenomics genotyping).

5. Variant testing for other factors, including but NOT limited to F9, MLP, prothrombin G1199A, PROC, PROS1, SERPINC1 (also known as PAI-1 gene), Factor V HR2 haplotype (F5 HR2), Factor VII R353Q ( F7 p.Arg353Gln), and/or Factor XIII V34L (e.g., Hereditary Thrombophilia Panel by Invitae Corp., Factor VII R353Q Mutation Analysis (16180X) by Quest Diagnostics Inc.) is Genetic Testing for Hereditary Thrombophilia

considered experimental and investigational to determine thrombophilia, including reflex testing following identification of member with the F5 p.Arg534Gln (FVL) variant.

6. Genetic testing that is marketed directly to consumers (direct-to-consumer or DTC) that are ordered by a member without the order of a treating health care provider is NOT covered.

7. Factor V Leiden testing is considered NOT medically necessary for ANY of the following indications, as specified below in items a through d:

a. Routine testing during pregnancy; OR

b. Prenatal and newborn screening; OR

c. Routine preimplantation genetic testing (with the Plan’s medical necessity guidelines specified in the Plan’s Preimplantation Genetic Testing medical policy, policy number OCA 3.726, rather than included in this policy); OR

d. Testing of individuals with arterial thrombosis;◊ OR

◊ Note: A member with arterial thrombosis should be screened for antiphospholipid antibodies. The antiphospholipid syndrome (APS) is characterized by thrombosis, recurrent fetal death, and the presence of circulating antiphospholipid antibodies. An individual with APS has an increased risk for both venous and arterial thrombosis.

8. Prior authorization requests for Factor V Leiden testing of neonates or children with catheter- related thrombosis require Plan Medical Director review and approval.

9. Multigene Panel Testing:

The use of a multigene testing panel is generally considered to be NOT medically necessary as an alternative to, or in addition to, factor V Leiden and prothrombin gene G20210A testing due to limited data on clinical validity and clinical utility of multigene testing. If the treating provider is recommending multigene panel testing rather than, or in addition to, the condition- targeted testing specified in the Medical Policy Statement section, Plan Medical Director review is required. For multigene panel testing to be considered medically necessary, medical record documentation must be submitted to the Plan with the prior authorization request demonstrating that ALL of the following criteria are met (and after approval by a Plan Medical Director), with criteria specified below in items a through g:

a. A recommendation for multigene panel testing for the member by an independent board- certified or board-eligible Medical Geneticist, an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor not employed by a commercial genetic testing laboratory, or a genetic nurse credentialed as either a Genetic Genetic Testing for Hereditary Thrombophilia

Clinical Nurse (GCN) or an Advanced Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory; this provider has a documented evaluation of the member which includes a completed 3- generation pedigree and intends to engage in post-test follow-up counseling; AND

b. Member meets criteria for genetic testing outlined in the Medical Policy Statement section of this policy AND

c. All genes included in the multigene panel are relevant to the personal medical history, biological family medical history, and/or treatment plan for the member being tested and there are professional society management guidelines or National Comprehensive National Comprehensive Cancer Network (NCCN) guidelines (with applicable references provided with the prior authorization request) documenting the clinical utility of testing for the members who test positive for any and all genes in the panel; AND

d. The results of the requested multigene panel will directly impact the treatment plan and clinical decision-making process for the member being tested; AND

e. There are no other known causative circumstances or factors (e.g., environmental exposures, injury, infection) that can explain the member’s symptoms or medical condition; AND

f. Multigene panel testing is more practical testing to diagnose the member’s condition than the separate single gene tests or targeted panels that would be recommended (with supporting documentation provided); AND

g. Clinical presentation of the member’s condition does not fit a well-described syndrome for which single-gene or targeted panel testing is available (e.g., comparative genomic hybridization/chromosomal microarray analysis) or single-gene or targeted panel testing is not clinically appropriate for the member’s condition (with supporting clinical documentation provided).

The Plan considers the multigene panel testing to be medically necessary only when ALL of the criteria outlined above (in items a through g) are met; disease-targeted genetic testing is considered medically necessary as an alternative when Plan criteria are met in the Medical Policy Statement section (and according to guidelines specified in the Limitations section of this policy). Review applicable InterQual® criteria (or the Plan’s Genetic/Genomic Testing and Pharmacogenetics medical policy, policy number OCA 3.727, when applicable InterQual® criteria are not available) for guidelines related to multigene panel testing to determine response to drug metabolism and adjuvant therapy and the use of multigene panels to determine hereditary cancer susceptibility for other types of cancer.

Genetic Testing for Hereditary Thrombophilia

Definitions Antiphospholipid Antibody Screening: Testing for antiphospholipid antibody syndrome, a condition in which the plasma levels of antibodies (including lupus anticoagulant, cardiolipin antibodies, or other antibodies against phospholipids) are elevated, adversely affecting coagulation processes in the bloodstream. Antiphospholipid antibody syndrome is a cause of acquired thrombophilia.

Antiprothrombin III Deficiency: Antiprothrombin III is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. Congenital antithrombin III deficiency is an autosomal dominant disorder in which an individual inherits at least one copy of a defective gene, leading to increased risk of venous and arterial thrombosis.

Cerebral Venous Sinus Thrombosis/Cerebral Sinovenous Thrombosis: A type of stroke that occurs when a blood clot forms in the brain’s venous sinuses. This prevents blood from draining out of the brain and a hemorrhage forms in the brain tissues. The condition may occur in adults or children (including fetuses and neonates).

F5 HR2 Haplotype: A group of linked F5 gene variants collectively known as the HR2 haplotype that has been the subject of investigation regarding its association with thrombophilia, alone and in conjunction with p.Arg534Gln (FVL).

Factor V Leiden (FVL) Gene Mutation p.Arg534Gln/Factor V (F5) Gene Variants: Factor V Leiden results from a point mutation that causes an amino acid change at position 534 in factor V (F5) of the protein (p.Arg534Gln) and is a common genetic defect related to hereditary (inherited) thrombophilia. “All of the following refer to the same variant (point mutation) in the F5 gene, which encodes factor V: Factor V Leiden (FVL); factor V p.Arg534Gln or R534Q (previously designated p.Arg506Gln or R506Q), a protein sequence change; and F5 c.1601G>A (previously designated c.1691G>A), a DNA sequence change.” (Bauer KA. UpToDate 2019.)

First-Degree Relative: A blood relative of an individual who shares approximately 50% of their genes defined as a parent, full sibling, and children.

Genetic Testing: According to U.S. Library of Medicine, genetic testing is defined as a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed. Several methods can be used for genetic testing:

1. Molecular genetic tests (or gene tests) study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.

Genetic Testing for Hereditary Thrombophilia

2. Chromosomal genetic tests analyze whole chromosomes to see if there are large genetic changes, such as an extra copy of a chromosome or missing DNA, that cause a genetic condition.

3. Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.

Multigene Panel Tests: Tests that evaluate more than one (1) gene simultaneously to detect changes in these genes’ sequence and expression most commonly associated with certain diseases and other genes that may have limited evidence of an association to the disorder. Multigene panel tests may involve traditional exon-by-exon sequencing of targeted genes to identify genetic variants or use next- generation sequencing. Each laboratory establishes its own set of criteria for selecting the genes represented in a panel, even when panels are used for the same or similar clinical indications. The lack of regulatory oversight of genetic testing means that laboratories can change the components of a panel at any time, making it difficult to evaluate the clinical utility of multigene panel tests.

Next-Generation Sequencing (NGS or Massively Parallel Sequencing): Genetic testing that involves sequencing of millions of DNA fragments using the following three (3) levels of molecular analysis: (1) Disease-targeted gene panels to sequence genes with an established role in the targeted disease, (2) exome sequencing of coding regions of the genome to include less common variants associated with the disease (i.e., a coding region is the segment of a gene that contains a protein-coding sequence called an exon in all 22,000 genes of the human genome); and (3) genome sequencing of both the coding and non-coding regions of the genome (i.e., the non-coding regions in between exons are called introns). Multiple sequencing platforms and different processes result in variability in test results among laboratories.

Protein C Deficiency: Protein C is a vitamin K-dependent protein synthesized in the liver. The gene for protein C is located on chromosome 2 (2q13-14) and appears to be closely related to the gene for factor IX. A deficiency in protein C predisposes an individual to thrombophilia.

Protein S Deficiency: Protein S is a vitamin K-dependent glycoprotein, is a cofactor of the protein C system. In the presence of protein S, activated protein C directly inhibits prothrombin activation via interactions with other coagulation factors. Two homologous genes for protein S (gene PROS1 and PROS2) map to chromosome 3. A deficiency in protein S predisposes an individual to thrombophilia.

Prothrombin Gene G20210A Mutation/Factor II (F2) Gene Variants: A mutation in the human prothrombin gene related to hereditary (inherited) thrombophilia. Prothrombin (factor II) is a vitamin K-dependent protein which is the precursor of thrombin, the end-product of the coagulation cascade. Prothrombin gene G20210A mutation is the second most common inherited thrombophilia after factor V Leiden.

Genetic Testing for Hereditary Thrombophilia

Single Nucleotide Polymorphisms (SNPs): The most common type of genetic variation among individuals. Each SNP represents a difference in a single DNA building block, called a nucleotide. SNPs occur normally throughout a person’s DNA; normally these variations are found in the DNA between genes. If more than one (1) percent of a population does not carry the same nucleotide at a specific position in the DNA sequence, then this variation can be classified as a SNP. Most SNPs have no effect on health or development. When there is sufficient scientific evidence to support the clinical utility of testing, SNPs may help predict an individual’s response to certain drugs, susceptibility to environmental factors, risk of developing particular diseases, and/or susceptibility to genetic diseases within families.

Thrombophilia: Hereditary and/or acquired conditions that are risk factors for venous thrombosis.

Venous Thrombosis: A clot present in a blood vessel. The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism (PE).

Applicable Coding The Plan uses and adopts up-to-date Current Procedural Terminology (CPT) codes from the American Medical Association (AMA), International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) diagnosis codes developed by the World Health Organization and adapted in the United Stated by the National Center for Health Statistics (NCHS) of the Centers for Disease Control under the U.S. Department of Health and Human Services, and the Health Care Common Procedure Coding System (HCPCS) established and maintained by the Centers for Medicare & Medicaid Services (CMS). Since the AMA, NCHS, and CMS may update codes more frequently or at different intervals than Plan policy updates, the list of applicable codes included in this Plan policy is for informational purposes only, may not be all inclusive, and is subject to change without prior notification. Whether a code is listed in the Applicable Coding section of this Plan policy does not constitute or imply member coverage or provider reimbursement. Providers are responsible for reporting all services using the most up-to-date industry-standard procedure and diagnosis codes as published by the AMA, NCHS, and CMS at the time of the service.

Providers are responsible for obtaining prior authorization for the services specified in the Medical Policy Statement section and Limitation section of this Plan policy, even if an applicable code appropriately describing the service that is the subject of this Plan policy is not included in the Applicable Coding section of this Plan policy. Coverage for services is subject to benefit eligibility under the member’s benefit plan. Refer to the member’s benefits document in effect at the time of the service to determine coverage or non-coverage as it applies to an individual member. See the Plan’s reimbursement policies for Plan billing guidelines.

Refer to the Medical Policies page of the Provider folder at www.bmchp.org (for BMC HealthNet Plan members, including Senior Care Options members) or www.wellsense.org (for Well Sense Health Plan members) for information about additional, condition-specific genetic testing and gene expression Genetic Testing for Hereditary Thrombophilia

profiling policies. Plan prior authorization is required for all genetic testing, even when the applicable code for the genetic test is not listed in a Plan policy.

CPT Codes Description: Codes Covered When Medically Necessary 81240 F2 (prothrombin, coagulation factor II) (e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant 81241 F5 (coagulation factor V) (e.g., hereditary hypercoagulability) gene analysis, Leiden variant

Clinical Background Information Hypercoagulability, or thrombophilia, leads to the inappropriate formation of blood clots, and most commonly manifests as venous thromboembolism (VTE), such as deep vein thrombosis (DVT) in the legs, pulmonary embolism (PE), or in women (including individuals born with female reproductive organs and/or with typical female karyotype with two [2] X chromosomes), as adverse pregnancy outcomes. VTE affects approximately 300,000 to 600,000 individuals each year in the United States; the annual incidence of first-time VTE is approximately 1 per 1000 individuals. Venous thromboembolism, including deep vein thrombosis and/or pulmonary embolism affects approximately 300,000 to 600,000 individuals in the United States annually. Typical precipitating factors for VTE include major trauma, recent surgery, immobilization, high body mass index (BMI), fractures, medical illness, or aging. Among women (including individuals born with female reproductive organs and/or with typical female karyotype with two [2] X chromosomes), risk is increased during pregnancy and use of oral contraceptives or hormone replacement therapy (HRT). Once diagnosed, treatment options include initial short-term anticoagulation that may be extended (e.g., lifetime therapy) based on risk of recurrence balanced with risk of major hemorrhage. Heritable genetic factors also contribute to the risk of VTE.

Inherited thrombophilias include the following abnormalities: Activated protein C resistance (factor V Leiden mutations), protein C deficiency, protein S deficiency, prothrombin deficiency, and prothrombin gene mutation. The most common type of inherited thrombophilia is a factor V Leiden (FVL) mutation (F5 gene variant p.Arg534Gln), which accounts for up to 50% of the inherited thrombophilia syndromes; deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases.

A key part of the clotting mechanism in the factor V protein is the activation of prothrombin to thrombin, which is required for the conversion of soluble fibrinogen to insoluble fibrin. A common sequence variant of the prothrombin gene, G20210A (c.*96G>A), is associated with elevated plasma prothrombin levels, which is also a risk factor for VTE. The discovery of FVL and prothrombin G20210A as primary causes of familial thrombosis has remarkably influenced genetic testing among patients with VTE or recurrent obstetric complications.

Genetic predisposition to hyperhomocysteinemia, which is associated with vascular disease and VTE, may be caused by the C677T (c.677C>T) sequence variant of the methylenetetrahydrofolate reductase Genetic Testing for Hereditary Thrombophilia

(MTHFR) gene located on chromosome 1 at band p36. There is insufficient published scientific evidence to support the clinical utility of MTHFR genetic testing to diagnose thrombophilia.

A group of gene variants linked to factor V Leiden, collectively known as the HR2 haplotype (Factor V HR2), has been studied for its possible association with thrombophilia, alone and in conjunction with p.Arg534Gln (FVL) gene variant. There is insufficient scientific evidence at this time to support factor V (F5) HR2 haplotype testing to identify hypercoagulability.

Genetic susceptibility may help explain VTE in general; however, it is important to note that many individuals who carry a genetic variant associated with thrombosis may never develop thrombotic event(s) even in the presence of an obvious precipitating factor. At the current time, there is insufficient scientific evidence in the peer reviewed medical literature to support the effectiveness of genetic testing for thrombophilia to treat individuals taking oral contraceptives, asymptomatic individuals, or individuals with first VTE with no family history remain unproven. Additional studies are needed to establish the clinical benefits on health outcomes for these indications.

The Food and Drug Administration (FDA) only regulates genetic tests sold as kits and has practiced enforcement discretion for laboratory-developed tests (LDTs), which represent the majority of genetic tests marketed in the United States. While the Centers of Medicare & Medicaid Services (CMS) does regulation the clinical laboratories in which LDTs are performed, CMS does not evaluate whether the genetic tests are clinically meaningful.

At the time of the Plan’s most recent policy review, the Centers for Medicare & Medicaid Services (CMS) has implemented the following national coverage determinations (NCDs) related to genetic testing: NCD for Colorectal Cancer Screening Tests (210.3) for coverage of immunoassay and guaiac fecal occult blood tests and the Cologuard™ - Multitarget Stool DNA (sDNA) test when CMS applicable criteria are met, NCD for Pharmacogenomic Testing for Warfarin Response (90.1) for medically necessary indications for testing as determined by CMS, and NCD for Cytogenetic Studies (190.3) for coverage based on CMS guidelines. CMS has determined that next generation sequencing (NGS) is reasonable and necessary as a diagnostic laboratory test and is covered nationally when performed in a CLIA-certified laboratory, when ordered by a treating physician, and when applicable CMS requirements are met, as specified in the CMS national coverage analysis (NCA) CAG-00450N. Medicare uses a combination of national and local coverage determinations for making coverage decisions for genetic tests. Medicare administrative contractors (MAC) may implement local coverage determinations (LCDs) that apply only within their own jurisdictions. Verify if applicable CMS criteria are in effect (through an NCD, LCD, or other CMS guidelines) for the specified genetic test, product name, site-specific gene analysis, and the indication for testing on the date of the prior authorization request for a Senior Care Options member.

Genetic Testing for Hereditary Thrombophilia

References Abu-Asab NS, Ayesh SK, Ateeq RO, Nassar SM, El-Sharif WA. Association of Inherited Thrombophilia with Recurrent Pregnancy Loss in Palestinian Women. Obstet Gynecol Int. 2011;2011:689684. Published online 2011 Jun 14. doi: 10.1155/2011/689684. PMID: 21765836.

American College of Medical Genetics and Genomics (ACMG). ACMG Board of Directors. Direct-to- consumer genetic testing: a revised position statement of the ACMGC. Genet Med. 2016 Feb;18(2):207-8. doi: 10.1038/gim.2015.190. Epub 2015 Dec 17. PMID: 26681314.

American College of Medical Genetics and Genomics (ACMG). ACMG News. ACMG Provides Recommendations on Genetic Testing Through the Choosing Wisely® Campaign. 2015 Jul 10. Accessed at: https://www.acmg.net//pdflibrary/acmg_choosingwisely_final.pdf

American College of Medical Genetics and Genomics (ACMG). Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA; ACMG Factor V Leiden Working Group. ACMG Consensus Statement on Factor V Leiden Mutation Testing. 2007 May 14. Accessed at: http://www.acmg.net/PDFLibrary/Factor-V-Ledien- Mutation-Testing.pdf

American College of Medical Genetics and Genomics (ACMG). Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153- 6. doi: 10.1038/gim.2012.165. Epub 2013 Jan 3. PMID: 23288205.

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Pruthi RK. Optimal utilization of thrombophilia testing. Int J Lab Hematol. 2017 May;39 Suppl 1:104-10. doi: 10.1111/ijlh.12672. PMID: 28447412.

Raffini L. Thrombophilia testing in children and adolescents. UpToDate. 2019 Oct 15. Accessed at: https://www.uptodate.com/contents/thrombophilia-testing-in-children-and-adolescents

Rennert H, DeSimone RA. Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects, Third Edition, 2019. Elsevier Inc. ISBN 978-0-12-813726-0. Doi:10.1016/C2015-0-05783-5. Accessed at: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/factor-v-leiden

Saracco P, Bagna R, Gentilomo C, Magarotto M, Viano A, Magnetti F, Giordano P, Luciani M, Molinari AC, Suppiej A, Ramenghi LA, Simioni P; Neonatal Working Group of Registro Italiano Trombosi Infantili (RITI). Clinical Data of Neonatal Systemic Thrombosis. J Pediatr. 2016 Apr;171:60-6. doi: 10.1016/j.jpeds.2015.12.035. Epub 2016 Jan 16. PMID: 26787378.

Sarecka-Hujar B, Kopyta I, Skrzypek M, Sordyl J. Association Between the 20210G>A Prothrombin Gene Polymorphism and Arterial Ischemic Stroke in Children and Young Adults-Two Meta-analyses of 3586 Cases and 6440 Control Subjects in Total. Pediatr Neurol. 2017 Apr;69:93-101. doi: 10.1016/ j.pediatrneurol.2016.12.013. Epub 2017 Jan 4. PMID: 28160964.

Saxonhouse MA. Thrombosis in the Neonatal Intensive Care Unit.Clin Perinatol. 2015 Sep;42(3):651-73. doi: 10.1016/j.clp.2015.04.010. PMID: 26250924.

Schnick P. Hereditary and Acquired Hypercoagulability. Medscape. 2020 Jun 2. Accessed at: https://emedicine.medscape.com/article/211039-overview

Segal JB, Brotman DJ, Emadi A, Necochea AJ, Samal L, Wilson LM, Crim MT, Bass EB. Outcomes of genetic testing in adults with a history of venous thromboembolism. Evid Rep Technol Assess (Full Rep). 2009 Jun;(180):1-162. PMID: 20629476.

Segers K, Dahlbäck B, Nicolaes GA. Coagulation factor V and thrombophilia: background and mechanisms. Thromb Haemost. 2007 Sep;98(3):530-42. PMID: 17849041.

Genetic Testing for Hereditary Thrombophilia

Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet. 2015 Mar;291(3):671-9. doi: 10.1007/s00404-014-3443-x. Epub 2014 Sep 6. PMID: 25193429.

Shen YM, Tsai J, Taiwo E, Gavva C, Yates SG, Patel V, Frenkel E, Sarode R. Analysis of Thrombophilia Test Ordering Practices at an Academic Center: A Proposal for Appropriate Testing to Reduce Harm and Cost. PLoS One. 2016 May 13;11(5):e0155326. doi: 10.1371/journal.pone.0155326. eCollection 2016. PMID: 27176603.

Silver RM, Saade GR, Thorsten V, Parker CB, Reddy UM, Drews-Botsch C, Conway D, Coustan D, Dudley DJ, Bukowski R, Rowland Hogue CJ, Pinar H, Varner MW, Goldenberg R, Willinger M. Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol. 2016 Oct;215(4):468.e1-468.e17. doi: 10.1016/j.ajog.2016.04.026. Epub 2016 Apr 27. PMID: 27131585.

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Genetic Testing for Hereditary Thrombophilia

Policy History Original Effective Original Policy Original Approval Date Date* and Policy Owner Approved by Version Number Regulatory Approval: N/A 03/01/14 Medical Policy MPCTAC and QIC Version 1 Manager as Chair of Internal Approval: MPCTAC 11/20/13: Medical Policy, Criteria, and Technology Assessment Committee (MPCTAC) 12/03/13: MPCTAC (electronic vote) 12/19/13: Quality Improvement Committee (QIC) *Effective Date for the Senior Care Options Product(s): 01/01/16

Policy Revisions History Revision Effective Date Review Date Summary of Revisions Approved by and Version Number 11/01/14 Review for effective date 03/01/15. 03/0/15 11/19/14: MPCTAC Revised criteria in the Medical Policy Version 2 12/10/14: QIC Statement and Limitations sections. Updated Summary, Definitions, and References sections. Changed review calendar. 11/01/15 Review for effective date 01/01/16. 01/01/16 11/18/15: MPCTAC Updated template with list of Version 3 11/25/15: MPCTAC applicable products and notes. (electronic vote) Updated Summary and language in the 12/09/15: QIC Applicable Coding section without changing criteria or the applicable code list. 01/01/16 Review for effective date 05/01/16. 05/01/16 01/20/16: MPCTAC Updated Description of Item or Service, Version 4 02/10/16: QIC Definitions, Clinical Background Information, and References sections. Revised criteria in the Limitations section. 09/28/16 Review for effective date 11/01/16. 11/01/16 09/30/16: MPCTAC Administrative changes to clarify Version 5 (electronic vote) language related to gender. 10/12/16: QIC 01/01/17 Review for effective date 05/01/17. 05/01/17 01/18/17: MPCTAC Updated Summary, Definitions, Clinical Version 6 02/08/17: QIC

Genetic Testing for Hereditary Thrombophilia

Policy Revisions History Background Information, References, and References to Applicable Laws and Regulations sections. Revised criteria in the Medical Policy Statement and Limitations sections. 01/01/18 Review for effective date 04/01/18. 04/01/18 01/17/18: MPCTAC Updated Definitions and References Version 7 sections. Revised Medical Policy Statement and Limitations sections. Updated Plan note in the Applicable Coding section. 01/01/19 Review for effective date 04/01/19. 04/01/19 01/16/19: MPCTAC Administrative changes made to the Version 8 Policy Summary, Limitations, Definitions, Applicable Coding, Clinical Background Information, References, Other Applicable Policies, and Reference to Applicable Laws and Regulations sections. Criteria revised in the Medical Policy Statement section. 07/01/19 Review for effective 10/01/19. 10/01/19 07/17/19: MPCTAC Administrative changes made to the Version 9 Policy Summary, Limitations, Applicable Coding, References, and Other Applicable Policies sections. 01/01/20 Review for effective date 04/01/20. 04/01/20 01/15/20: MPCTAC Criteria revised in the Limitations Version 10 section. Administrative changes made to the Medical Policy Statement, Definitions, Clinical Background Information, References, and Reference to Applicable Laws and Regulations sections. 02/01/21 Review for effective date 03/01/21. 03/01/21 02/17/21: MPCTAC Administrative changes made to the Version 11 Policy Summary, Medical Policy Statement, Limitations, Definitions, Clinical Background Information, and References sections.

Last Review Date 02/01/21

Genetic Testing for Hereditary Thrombophilia

Next Review Date 01/01/22

Authorizing Entity MPCTAC

Other Applicable Policies Medical Policy - Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies, policy number OCA 3573 Medical Policy - Experimental and Investigational Treatment, policy number OCA 3.12 Medical Policy - Genetic Testing for Fragile X-Associated Disorders, policy number OCA 3.571 Medical Policy - Genetic/Genomic Testing and Pharmacogenetics, policy number OCA 3.727 Medical Policy - Medically Necessary, policy number OCA 3.14 Medical Policy - Preimplantation Genetic Testing, policy number OCA 3.726 Reimbursement Policy - General Billing and Coding Guidelines, policy number 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number SCO 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number WS 4.17 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number SCO 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number WS 4.18 Reimbursement Policy - Non-Participating Provider, policy number WS 4.5 Reimbursement Policy - Non-Reimbursed Codes, policy number 4.38 Reimbursement Policy - Non-Reimbursed Codes, policy number WS 4.38 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number 4.608 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number SCO 4.608 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number WS 4.28

Reference to Applicable Laws and Regulations 21 CFR § 864.7280. Code of Federal Regulations. Title 21 Food and Drugs. Food and Drug Administration. Medical Devices. Hematology and Pathology Devices. Factor V Leiden DNA mutation detection systems.

42 CFR § 438.210. Code of Federal Regulations. Title 42 Public Health. Medical Assistance Programs. Managed Care Access Standards. Coverage and Authorization of Services.

78 FR 48164-69. Federal Regulations. Centers for Medicare and Medicaid Services (CMS). Medicare Program. Revised Process for Making National Coverage Determinations. 2013 Aug 7. Genetic Testing for Hereditary Thrombophilia

Commonwealth of Massachusetts. General Laws. Accessed at: https://malegislature.gov/Laws/GeneralLaws

He-W 500. New Hampshire Code of Administrative Rules. Medical Assistance.

He-W 530.01(e). New Hampshire Code of Administrative Rules. Medical Assistance. Service Limits, Co- Payments, and Non-Covered Services. Definitions. Medically Necessary.

He-W 531. New Hampshire Code of Administrative Rules. Medical Assistance. Physician Services.

He-W 543. New Hampshire Code of Administrative Rules. Medical Assistance. Hospital Services.

MGL ch 111 § 70G. Massachusetts General Law. Genetic information and reports protected as private information; prior written consent for genetic testing.

MGL c 1760. Massachusetts General Laws. Health Insurance Consumer Protections.

New Hampshire Department of Health and Human Services (DHHS). Certified Administrative Rules. Accessed at: https://www.dhhs.nh.gov/oos/bhfa/rules.htm

RSA 326-K. New Hampshire Revised Statutes Annotated. Genetic Counselors.

RSA 420-E. New Hampshire Revised Statutes Annotated. Insurance. Licensure of Medical Utilization Review Entitles.

Disclaimer Information: + Medical Policies are the Pla+n’s guidelines for determining the medical necessity of certain services or supplies for purposes of determining coverage. These Policies may also describe when a service or supply is considered experimental or investigational, or cosmetic. In making coverage decisions, the Plan uses these guidelines and other Plan Policies, as well as the Member’s benefit document, and when appropriate, coordinates with the Member’s health care Providers to consider the individual Member’s health care needs. Plan Policies are developed in accordance with applicable state and federal laws and regulations, and accrediting organization standards (including NCQA). Medical Policies are also developed, as appropriate, with consideration of the medical necessity definitions in various Plan products, review of current literature, consultation with practicing Providers in the Plan’s service area who are medical experts in the particular field, and adherence to FDA and other government agency policies. Applicable state or federal mandates, as well as the Member’s benefit document, take precedence over these guidelines. Policies are reviewed and updated on an annual basis, or more frequently as needed. Treating providers are solely responsible for the medical advice and treatment of Members. The use of this Policy is neither a guarantee of payment nor a final prediction of how a specific claim(s) will be adjudicated. Reimbursement is based on many factors, including member eligibility and benefits on the date of service; medical necessity; utilization management guidelines (when applicable); coordination of benefits; adherence with applicable Plan policies and procedures; clinical coding criteria; claim editing logic; and the applicable Plan – Provider agreement.

Genetic Testing for Hereditary Thrombophilia