Please refer to CMS website for the most current applicable National Coverage Determination (NCD)/ Local Coverage Determination (LCD)/Local Coverage Article (LCA)/CMS Online Manual System/Transmittals.

Genetic and Coagulation Testing for Noncancer Blood Disorders

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Billing and Coding: MolDX: HBB Gene Tests
AS54267
A54267
LCD
MolDX: Biomarkers in Cardiovascular Risk Assessment
L36129

Genetic and Coagulation Testing for Noncancer Blood Disorders

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Billing and Coding: MolDX: HBB Gene Tests
LCD
MolDX: Biomarkers in Cardiovascular Risk Assessment
L36362

Genetic and Coagulation Testing for Noncancer Blood Disorders

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Billing and Coding: MolDX: HBB Gene Tests
LCD
MolDX: Biomarkers in Cardiovascular Risk Assessment
L36362
JF - Noridian Healthcare Solutions, LLC
AK, AZ, ID, MT, ND, OR, SD, UT, WA, WY

Genetic and Coagulation Testing for Noncancer Blood Disorders

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Description
Blood disorders can affect any of the three main components of blood including erythrocytes (red blood cells [RBCs]), leukocytes (white blood cells [WBCs]), thrombocytes (platelets) or tissues where these are formed (bone marrow, lymph nodes and spleen).
Coagulation (blood clotting) disorders are defects in the liver’s ability to make sufficient amounts of proteins (eg, fibrinogen, prothrombin) needed to assist in the formation of blood clots and can result in hemorrhage (too little clotting) or thrombosis (too much clotting).

Blood and coagulation disorders may be acquired (caused by disease or side effects of medication) or inherited (caused by genes). Most bleeding and clotting disorders are caused by abnormalities in hemostasis (eg, dysfunction of platelets and/or clotting proteins). Less commonly, excessive bleeding or clotting can be caused by abnormalities in the fibrinolytic system (fibrinolysis). Atypical hemolytic uremic syndrome (aHUS) is a disorder that causes abnormal blood clots to form in small blood vessels in the kidneys or other parts of the body (thrombotic microangiopathy [TMA]). These clots can restrict or block blood flow causing hemolytic anemia, thrombocytopenia and kidney failure. aHUS can occur at any age and often results from a combination of acquired and inherited factors.

G6PD gene testing has been proposed to detect pathogenic variants for the diagnoses of hemolytic anemia and jaundice which is associated with G6PD enzyme deficiency.

Blood group antigens play a role in recognizing foreign cells in the bloodstream. If a blood type mismatch occurs during a blood transfusion it could lead to an immune response and possible illness. RBC antigen genotyping assays have been proposed as an alternative approach to determining compatibility of donated blood. Blood group genotyping purportedly overcomes blood grouping limitations by looking directly into the DNA sequence and thereby avoiding any donor cell or antibody interference.

Bone marrow failure syndromes (BMFS) are rare diseases that occur in an individual who produces an insufficient amount of red blood cells, white blood cells or platelets and may be acquired or inherited. Inherited BMFS occurs from germline mutations that are passed down from parents. The majority are inherited in an autosomal recessive manner (eg, Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, reticular dysgenesis) while a small subset is inherited in X-linked recessive (eg, dyskeratosis congenita) or autosomal dominant patterns (eg, Blackfan-Diamond anemia, reticular dysgenesis). Large multigene panels have been proposed to diagnose these disorders.

Hemoglobinopathies are a group of inherited blood disorders that primarily affect RBCs causing abnormal production or structure of the hemoglobin molecule. They are inherited single-gene disorders and include sickle cell anemia, alpha- and beta-thalassemias.

Methylene tetrahydrofolate reductase (MTHFR) enzyme is encoded by the MTHFR gene. This enzyme plays a role in processing amino acids (the building blocks of proteins) which is important for a chemical reaction involving forms of the vitamin folate and is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds. Variations in the MTHFR gene have been studied as risk factors for numerous conditions, including behavioral disorders, cardiovascular disease, thrombophilia, stroke, hypertension,

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pharmacological management or risk testing and pregnancy-related complications; however, its role remains unclear.

Neutropenia is a condition characterized by abnormally low levels of neutrophils, a type of white blood cell that is mainly produced in the bone marrow. Most causes of neutropenia are acquired (eg, autoimmune disorders, infection, side effects of medication/chemotherapy) with congenital neutropenia being less common.

Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis, the clot dissolving portion of the coagulation process. PAI-1 is under investigation as a risk factor for conditions such as cardiovascular disease, thrombophilia and pregnancy-related complications.

The PAI-1 test is an antibody-based enzyme assay.

Sickle cell disease (SCD) is an autosomal recessive genetic condition that alters the shape and function of the hemoglobin molecule in RBCs. SCD is characterized by frequent and unpredictable vaso-occlusive complications (VOCs) that result from reduced blood flow in the microvasculature, including red cell stickiness and erythrocyte sickling. These processes lead to pain, chronic organ damage and decreased life expectancy. Flow-based adhesion and mechanical fragility assays are proposed to measure possible biomarkers associated with anemia/hemolysis, cellular adhesion, cellular aggregates, inflammation, coagulation, microparticles and nitric oxide metabolism during a VOC state to help assess an individual’s response to disease modifying therapy.

Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes in the blood that can lead to hypocoagulation. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) (fetomaternal alloimmune thrombocytopenia [FMAIT]) is the most common cause of severe thrombocytopenia in a fetus or newborn. This occurs when inherited platelet antigens from the mother and father are incompatible, resulting in fetal platelet destruction. Maternal and paternal human platelet antigen (HPA) genotyping is commonly used to confirm a diagnosis. Heparin-induced thrombocytopenia (HIT) is a rare immune response to the drug heparin (a blood thinning medication) and is associated with arterial and venous thrombosis.

Thrombophilia (also known as hypercoagulability) is a disorder of blood coagulation that increases the risk for blood clots (thrombosis) in veins or arteries. Thrombophilia can be acquired or inherited. The most common acquired thrombophilias occur as a result of injury, surgery or a medical condition. The most common hereditary thrombophilias are factor V Leiden (FVL), due to a variant in the F5 gene and prothrombin G20210A, as a result of a variant in the F2 gene.

Von Willebrand disease (VWD) is the most common inherited blood clotting disorder and affects approximately 1 in 100 individuals. VWD is caused by deficient or defective plasma von Willebrand factor (VWF), a large multimeric glycoprotein that assists with primary hemostasis to prevent and stop bleeding. VWD is most commonly characterized by mucocutaneous (eg, epistaxis, genitourinary, gastrointestinal, gingival or petechiae) bleeding. The types of inherited VWD include type 1, type 2 (contains various subtypes), type 3 and platelet type. Acquired Von Willebrand syndrome (aVWS) is less common and may be associated with the use of extracorporeal membrane oxygenation (ECMO) or left ventricular assist devices (LVAD). Conditions such as aortic stenosis, autoimmune disorders (eg, antiphospholipid antibody syndrome, scleroderma and systemic lupus erythrematosus), congenital cardiac anomalies or myeloproliferative neoplasms may also contribute to aVWS.

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Multigene (or expanded) panels analyze a broad set of genes simultaneously (as opposed to single gene testing that searches for variants in one specific gene) and have been proposed to evaluate the DNA of an individual with a personal and/or family history of more than one hereditary condition or syndrome or hereditary conditions/syndromes associated with more than one gene. Panels often include medically actionable genes but may also include those with unclear medical management.

Targeted (or focused) multigene panels analyze a limited number of genes targeted to a specific condition.

Coverage Determination

Humana follows the CMS requirement that only allows coverage and payment for services that are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member except as specifically allowed by Medicare.

Genetic tests must demonstrate clinical utility, analytical and clinical validity and fulfill the CMS “reasonable and necessary” criteria. Analytic validity (test accurately identifies the gene variant), clinical validity (test identifies or predicts the clinically defined disorder) and clinical utility (test measurably improves clinical outcomes) of the genetic test is supported by generally accepted standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, specialty society recommendations, and views of physicians practicing in relevant clinical areas. The test must be ordered by a physician who is treating the beneficiary and the results will be used in the management of a beneficiary’s specific medical problem.

For jurisdictions with no Medicare guidance for a particular test, Humana will utilize the MolDX program MolDX Program and Technical Assessments for molecular assays as the standard to evaluate clinical utility, analytical and clinical validity in conjunction with adhering to Medicare’s reasonable and necessary requirement.

In interpreting or supplementing the criteria above and in order to determine medical necessity consistently, Humana may consider the following criteria:

General Criteria for Genetic and Coagulation Testing for Noncancer Blood Disorders

Apply General Criteria for Genetic and Coagulation Testing for Noncancer Blood Disorders when disease- or gene-specific criteria are not available on this medical coverage policy.

Genetic and coagulation testing for noncancer blood disorders will be considered medically reasonable and necessary if:

• Individual to be tested is under active management or being evaluated for a noncancer blood disorder;
• Individual is within the population and has the indication for the test’s intended use;
• Results of testing must directly impact treatment or management of the Medicare beneficiary;
• Analytic validity, clinical validity and clinical utility of the genetic test is supported by the MolDX program;
• Test is ordered by a physician who is treating the individual

Criteria for Specific Noncancer Blood Disorders

GERMLINE (HEREDITARY) TESTING:

Alpha Thalassemia (HBA1 and HBA2 Genes)

HBA1/HBA2 gene testing will be considered medically reasonable and necessary for alpha thalassemia when the following requirements are met:

• HBA1/HBA2 deletion/duplication testing for individuals with a protein-based hemoglobin analysis suggestive of alpha thalassemia; OR
• Individual to be tested has equivocal or indeterminate diagnosis based on results of prior testing such as complete blood count (CBC) and hemoglobin analysis by qualitative/quantitative electrophoresis, high performance liquid chromatography (HPLC) or isoelectric focusing; OR
• To establish disease-causing variant in an individual with a confirmed diagnosis

Testing strategy:
1. Targeted analysis for common deletions of HBA1 and HBA2
2. Perform sequence analysis of HBA1 and HBA2 if a common deletion of HBA1/2 is not identified
3.

Deletion/duplication analysis of HBA1, HBA2 and MCS-R2 for uncommon deletions may be performed next, if no pathogenic variant is identified with sequence analysis

Prothrombin G20210A Thrombophilia (F2 Gene) and Factor V Leiden (FVL) Thrombophilia (F5 Gene)

F2 and F5 gene testing for prothrombin G20210A thrombophilia factor II and factor V Leiden (FVL) thrombophilia will be considered medically reasonable and necessary for pregnant individuals when all the following requirements are met: 29,39-42

• Individual has a personal history of venous thromboembolism (VTE) associated with a nonrecurrent risk factor (eg, surgery, trauma); AND
• Individual is not currently receiving anticoagulant prophylaxis; AND
• Results of genetic testing will inform risk stratification for VTE recurrence and subsequent need for antenatal prophylaxis

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RBC Genotyping Assays

RBC Genotyping Assays will be considered medically reasonable and necessary when the following requirements are met: 8-12, 30-34

• Test is FDA approved and tests for multiple antigens (eg, 0001U and 0084U); AND
• Testing is being performed as part of a pre-transfusion evaluation for an individual who may require or is expected to require a blood product transfusion (leukocytes, platelets or RBCs) when conventional serologic testing methods are inadequate or at a high risk of producing unreliable or misleading results

The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms. Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy.

Coverage Limitations

US Government Publishing Office. Electronic code of federal regulations: part 411 – 42 CFR § 411.15 - Particular services excluded from coverage

The following test types are examples of testing services that may not be considered a benefit (statutory excluded) and denied as Medicare Excluded tests:

• FANCC gene testing (eg, 81242, 81412 and 81413);13-17 OR
• G6PD gene testing (eg, 81247, 81248 and 81249);38 OR
• HBB gene testing (eg, 81361, 81362, 81363, 81364, 81443);18-22 OR
• Human platelet antigen HPA-1a/b – 6a/b, 9a/b, 15a/b genotyping (eg, 81105 to 81112);8-12 OR
• Individual RBC antigen tests that are not part of a comprehensive antigen evaluation (eg, 0180U-0201U, 0221U, 0222U) or comprehensive panels that are not FDA approved (eg, 0246U, 0282U);8-12, 30-34 OR
• MTHFR gene testing (eg, 81291), individually or as part of a panel;39-43 OR
• Plasminogen activator inhibitor-1 (PAI-1) testing (85415)25-29
• Tests considered screening in the absence of clinical signs and symptoms of disease that are not specifically identified by the law;79 OR
• Tests that confirm a diagnosis or known information;79 OR
• Tests that investigate the same germline genetic content, for the same genetic information, that has already been tested in the same individual; 8-12, 30-34 OR
• Tests to determine risk for developing a disease or condition;79 OR
• Tests performed to measure the quality of a process;79 OR
• Tests without diagnosis specific indications;79 OR
• Tests identified as investigational by available literature and/or the literature supplied by the developerand are not a part of a clinical trial79

These treatments and services fall within the Medicare program’s statutory exclusion that prohibits payment for items and services that have not been demonstrated to be reasonable and necessary for the diagnosis and treatment of illness or injury (§1862(a)(1) of the Act).

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Other services/items fall within the Medicare program’s statutory exclusion at 1862(a)(12), which prohibits payment. Genetic tests that have not demonstrated clinical utility, analytical and clinical validity via the MolDX Program will not be considered medically reasonable and necessary. A review of the current medical literature shows that the evidence is insufficient to determine that these services are standard medical treatments. There remains an absence of randomized, blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of these services in clinical management.

The following genetic and coagulations tests for noncancer blood disorders are considered not medically reasonable and necessary for any indication:

• Flow-based adhesion or mechanical fragility assays (0121U, 0122U, 0123U, 0303U, 0304U and 0305U)
• Versiti Heparin-Induced Thrombocytopenia Evaluation – PEA (0275U)
• Versiti VWF Collagen III Binding (0279U)
• Versiti VWF Collagen IV Binding (0280U)
• Versiti VWF Propeptide Antigen (0281U)
• Versiti VWD Type 2B Evaluation (0283U)
• Versiti VWD Type 2N Binding (0284U)

A review of the current medical literature shows that the evidence is insufficient to determine that these services are standard medical treatments. There remains an absence of randomized, blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of these services in clinical management.

Genetic Testing for Inherited Thrombophilias (F2 and F5 Genes)

The Medicare guidelines state that genetic testing for the F2 and F5 genes for cardiovascular risk assessment is not medically necessary as it is unlikely to impact clinical management except in pregnant individuals.

There is no Medicare benefit for assessment of thrombosis risk in asymptomatic individuals (eg, screening for inherited thrombophilia) or in asymptomatic individuals that have a documented family history of inherited thrombophilia.

Multigene (or expanded) panels

are considered not medically reasonable and necessary for any indication unless ALL genes in the panel meet disease- or gene-specific criteria (Refer to Coverage Determination section or Limitations section for single genes in a panel). Examples include, but may not be limited to:

• Multigene (or expanded) panel testing for the diagnosis of inherited BMFS (81441)
• Versiti aHUS Genetic Evaluation (0268U)
• Versiti Autosomal Dominant Thrombocytopenia Panel (0269U)
• Versiti Coagulation Disorder Panel (0270U)
• Versiti Comprehensive Bleeding Disorder Panel (0272U)
• Versiti Comprehensive Platelet Disorder Panel (0274U)
• Versiti Congenital Neutropenia Panel (0271U)
• Versiti Fibrinolytic Disorder Panel (0273U)
• Versiti Inherited Thrombocytopenia Panel (0276U)
• Versiti Platelet Function Disorder Panel (0277U)
• Versiti Thrombosis Panel (0278U)

Summary of Evidence

Multigene Panels Versus Multigene (or Expanded) Panels including but not limited to, multiple genes or multiple conditions and in cases where a tiered approach/method is clinically available, testing would be covered only for the number of genes or test that are reasonable and necessary to establish a diagnosis.

Flow-based Adhesion or Mechanical Fragility Assays

The gold standard for assessment of the pain associated with Sickle cell disease is the individual’s (or family's) report of the pain severity and similarity to or difference from previous vaso-occlusive pain episodes. There are no specific laboratory findings associated with vaso-occlusive pain.