Humana Genetic and Coagulation Testing for Noncancer Blood Disorders Form

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)

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. (Refer to Coverage Limitations section)

Blood Group Antigens

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. (Refer to Coverage Limitations section)

Bone Marrow Failure Syndromes (BMFS)

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 mutigene panels have been proposed to diagnose these disorders. (Refer to Coverage Limitations section)

Hemoglobinopathies

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.

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Neutropenia

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)

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. (Refer to Coverage Limitations section)

For information regarding FVL, PAI-1, prothrombin genetic testing for cardiovascular disease, please refer to Genetic Testing for Cardiac Conditions Medical Coverage Policy.

Sickle cell disease (SCD)

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. (Refer to Coverage Limitations section)

Thrombocytopenia

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.⁵⁶ 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.

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017

Page: 4 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Thrombophilia

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)

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)

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.

For information regarding genetic testing for myeloproliferative neoplasms (MPNs), please refer to Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis and Genetic Testing for Diagnosis and Monitoring of Cancer Medical Coverage Policies.

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing
• Retrieved archival tissue

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017

Page: 5 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Coverage Determination

Any state mandates for genetic testing take precedence over this medical coverage policy.

Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding Plan coverage.

Apply General Criteria for Genetic and Pharmacogenomics Tests when disease- or gene-specific criteria are not available on a medical coverage policy. For information regarding General Criteria for Genetic and Pharmacogenomics Tests, please refer to Genetic Testing Medical Coverage Policy.

Alpha Thalassemia (HBA1 and HBA2 Genes)

Humana members may be eligible under the Plan for HBA1/HBA2 gene testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
  o Individual to be tested has a first-degree relative with confirmed diagnosis; OR
  o 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
  o To establish disease-causing variant in an individual with a confirmed diagnosis
• Testing strategy:
  1. Test for known familial variant (KFV) if known; OR
  2. If KVF testing has not been performed, then targeted analysis for common deletions of HBA1 and HBA2 may be pursued:
  a. Perform sequence analysis of HBA1 and HBA2 if a common deletion of HBA1/2 is not identified
  b.

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017

Page: 6 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

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

Beta Thalassemia and Sickle Cell Disease (Anemia) (HBB Gene)

Humana members may be eligible under the Plan for HBB gene testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
  o Individual to be tested has a first-degree relative with confirmed diagnosis; OR
  o 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
  o To establish disease-causing variant in an individual with a confirmed diagnosis
• Testing strategy:
  1. Test for known familial variant (KFV) if known; OR
  2. If KVF testing has not been performed, then Perform HBB gene sequence analysis
  a. Perform targeted deletion/duplication analysis of HBB gene if only 1 or no pathogenic variant is identified with sequence analysis

Factor V Leiden (FVL) Thrombophilia (F5 Gene)

Humana members may be eligible under the Plan for F5 gene testing for FVL thrombophilia when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Abnormal activated protein C (APC) resistance assay result, unless the individual presents with the following⁵⁵:
  o Has a known presence of lupus anticoagulant (lupus antibody, LA, LAC, lupus inhibitor); OR
  o Is receiving direct thrombin inhibitor therapy (eg, argatroban, dabigatran); OR
  o Is receiving factor Xa inhibitor therapy (eg, apixaban, rivaroxaban);
• AND ANY of the following:
  Asymptomatic female who is planning pregnancy or is currently pregnant and not taking anticoagulation therapy;
  AND EITHER of the following
  First-degree relative with a history of high-risk thrombophilia (eg, antithrombin deficiency, double heterozygosity or homozygosity for FVL or prothrombin G20210A); OR
  First-degree relative with venous thromboembolism (VTE) before age 50 years; OR
  First unprovoked (from an unknown cause) VTE at any age; OR
  Individual with a first VTE AND a first-degree relative with a VTE occurring before 50 years of age; OR
  Individual with history of recurrent VTE; OR
  Venous thrombosis at unusual sites (eg, cerebral, hepatic, mesenteric and portal veins);

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017
• Page: 7 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Genetic and Coagulation Testing for Noncancer Blood Disorders Effective Date: 07/07/2023 Revision Date: 07/07/2023 Review Date: 07/07/2023 Policy Number: HUM-0525-017 Page: 8 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

VTE associated with the use of oral contraceptives or hormone replacement therapy (HRT); OR

VTE during pregnancy or the puerperium

Human Platelet Antigen HPA-1a/b – 6a/b, 9a/b, 15a/b Genotyping

Humana members may be eligible under the Plan for HPA genotyping for FNAIT (FMAIT) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
  • Current or previous pregnancy with suspected or confirmed alloimmune thrombocytopenia; OR
  • Fetal or neonatal bleeding of unknown etiology (eg, intracranial hemorrhage, mucosal bleeding, petechiae); OR
  • Maternal serology positive for alloantibodies against fetal/neonatal platelet antigen; OR
  • Neonate with severe thrombocytopenia (eg, platelet count less than 50,000/µL); OR
  • Screening of an individual with a first-degree relative with alloimmune thrombocytopenia

Prothrombin G20210A Thrombophilia (F2 Gene)

Humana members may be eligible under the Plan for F2 gene testing for prothrombin G20210A thrombophilia when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Asymptomatic female who is planning pregnancy or is currently pregnant and not taking anticoagulation therapy; AND EITHER of the following:
  • First-degree relative with a history of high-risk thrombophilia (eg, antithrombin deficiency, double heterozygosity or homozygosity for FVL or prothrombin G20210A); OR
  • First-degree relative with VTE before 50 years of age; OR
  • First unprovoked (eg, from an unknown cause) VTE at any age; OR
  • Individual with a first VTE AND a first-degree relative with a VTE occurring before 50 years of age; OR
  • Individual with history of recurrent VTE; OR
  • Venous thrombosis at unusual sites (eg, cerebral, hepatic, mesenteric and portal veins); OR
  • VTE associated with the use of oral contraceptives or hormone replacement therapy (HRT); OR
  • VTE during pregnancy or the puerperium

Coverage Limitations

Humana members may NOT be eligible under the Plan for the following coagulation tests for any indication:

• 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)

All indications are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition.

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017
• Page: 10 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana members may NOT be eligible under the Plan for flow-based adhesion or mechanical fragility assays (0121U, 0122U, 0123U, 0303U, 0304U and 0305U) for any indication.

This technology is considered experimental/investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for G6PD gene testing (81247, 81248 and 81249) for any indication. This technology is considered experimental/investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for genetic testing for HPA genotyping for FNAIT (FMAIT) for any indications other than those listed above. This is considered experimental/investigational as it is not identified as widely used and generally accepted for any other proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for genetic testing for inherited hemoglobinopathies or thrombophilias for any indications other than those listed above. This is considered experimental/investigational as it is not identified as widely used and generally accepted for any other proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for multigene panel testing for the diagnosis of BMFS (81441). This technology is considered experimental/ investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for multigene panels 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).

• 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)

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for plasminogen activator inhibitor-1 (PAI-1) testing for any indication including pregnancy complications and VTE. This is considered experimental/investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for RBC antigen genotyping assays (eg, 0001U, 0084U, 0180U to 0201U, 0221U, 0222U, 0246U, 0282U) for any indication.

This technology is considered experimental/investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for genetic testing for noncancer blood disorders for any genes, indications or tests other than those listed above including:

• Individual to be tested has an affected first-, second- or third-degree relative with a negative genetic testing result for the associated condition
• KFV detection analysis using either of the following methods:
  • Genetic and Coagulation Testing for Noncancer Blood Disorders
  • Effective Date: 07/07/2023
  • Revision Date: 07/07/2023
  • Review Date: 07/07/2023
  • Policy Number: HUM-0525-017
  • Page: 12 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

o KFV analysis using a multigene panel that includes the KFV

o Sequencing, deletion/duplication analysis or large genomic rearrangement analysis (conducted individually, as comprehensive testing or sequentially) without KFV results of a first, second- or third-degree relative

These are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition.

Additional information about noncancer blood disorders may be found from the following websites:

Background

• National Library of Medicine

Medical Alternatives

Alternatives to G6PD gene testing include, but may not be limited to, the following:

• G6PD enzyme testing

Alternatives to RBC genotyping include, but may not be limited to, the following:

• ABO blood group and Rh factor identification
• Antibody screening
• RBC phenotype and crossmatching

Alternatives to whole blood flow adhesion and mechanical fragility assays include, but may not be limited to, the following:

• Complete blood count
• Reticulocyte count
• Urinalysis

Physician consultation is advised to make an informed decision based on an individual’s health needs.

Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017
• Page: 13 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes.

Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.

CPT® Code(s)

Description

Comments

• 81105 - Human Platelet Antigen 1 genotyping (HPA-1), ITGB3 (integrin, beta 3 [platelet glycoprotein Illa], antigen CD61 [GPllla]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post- transfusion purpura), gene analysis, common variant, HPA-1a/b (L33P)
• 81106 - Human Platelet Antigen 2 genotyping (HPA-2), GP1BA (glycoprotein Ib [platelet], alpha polypeptide [GPlba]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post- transfusion purpura), gene analysis, common variant, HPA-2a/b (T145M)
• 81107 - Human Platelet Antigen 3 genotyping (HPA-3), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/Illa complex], antigen CD41 [GPllb]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-3a/b (1843S)
• 81108 - Human Platelet Antigen 4 genotyping (HPA-4), ITGB3 (integrin, beta 3 [platelet glycoprotein Illa], antigen CD61 [GPllla]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post- transfusion purpura), gene analysis, common variant, HPA-4a/b (R143Q)

Genetic and Coagulation Testing for Noncancer Blood Disorders Effective Date: 07/07/2023 Revision Date: 07/07/2023 Review Date: 07/07/2023 Policy Number: HUM-0525-017 Page: 14 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• 81109 - Human Platelet Antigen 5 genotyping (HPA-5), ITGA2 (integrin, alpha 2 [CD49B, alpha 2 subunit of VLA-2 receptor] [GPla]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant (eg, HPA-5a/b (K505E))
• 81110 - Human Platelet Antigen 6 genotyping (HPA-6w), ITGB3 (integrin, beta 3 [platelet glycoprotein Illa, antigen CD61] [GPilla]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-6a/b (R489Q)
• 81111 - Human Platelet Antigen 9 genotyping (HPA-9w), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/Illa complex, antigen CD41] [GPllb]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-9a/b (V837M)
• 81112 - Human Platelet Antigen 15 genotyping (HPA-15), CD109 (CD109 molecule) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-15a/b (S682Y)
• 81240 - F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant
• 81241 - F5 (coagulation factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant
• 81247 - G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; common variant(s) (eg, A, A-) - Not Covered
• 81248 - G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; known familial variant(s) - Not Covered
• 81249 - G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; full gene sequence - Not Covered
• 81257 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, Constant Spring)

Genetic and Coagulation Testing for Noncancer Blood Disorders Effective Date: 07/07/2023 Revision Date: 07/07/2023 Review Date: 07/07/2023 Policy Number: HUM-0525-017 Page: 15 of 29

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

CPT® Code(s)

Description

Comments

• 81258 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant
• 81259 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence
• 81269 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants
• 81361 - HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (eg, HbS, HbC, HbE)
• 81362 - HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s)
• 81363 - HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s)
• 81364 - HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence
• 81441 - Inherited bone marrow failure syndromes (IBMFS) (eg, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, GATA2 deficiency syndrome, congenital amegakaryocytic thrombocytopenia) sequence analysis panel, must include sequencing of at least 30 genes, including BRCA2, BRIP1, DKC1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, GATA1, GATA2, MPL, NHP2, NOP10, PALB2, RAD51C, RPL11, RPL35A, RPS10, RPS19, RPS24, RPS26, RPS7, SBDS, TERT, and TINF2 - Not Covered New Code Effective 01/01/2023
• 85415 - Fibrinolytic factors and inhibitors; plasminogen activator - Not Covered if used to report any test outlined in Coverage Limitations section

86022Antibody identification; platelet antibodiesGenetic and Coagulation Testing for Noncancer Blood Disorders Effective Date: 07/07/2023 Revision Date: 07/07/2023 Review Date: 07/07/2023 Policy Number: HUM-0525-017 Page: 16 of 29

Refer to Medical and Pharmacy Coverage Policies to verify this is the current version before utilizing.

96040

Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family

• 0001U - Red blood cell antigen typing, DNA, human erythrocyte antigen gene analysis of 35 antigens from 11 blood groups, utilizing whole blood, common RBC alleles reported - Not Covered
• 0084U - Red blood cell antigen typing, DNA, genotyping of 10 blood groups with phenotype prediction of 37 red blood cell antigens - Not Covered
• 0121U - Sickle cell disease, microfluidic flow adhesion (VCAM-1), whole blood - Not Covered
• 0122U - Sickle cell disease, microfluidic flow adhesion (P-selectin), whole blood - Not Covered
• 0123U - Mechanical fragility, RBC, shear stress and spectral analysis - profiling - Not Covered
• 0180U - Red cell antigen (ABO blood group) genotyping (ABO), gene analysis Sanger/chain termination/conventional sequencing, ABO (ABO, alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase) gene, including subtyping, 7 exons - Not Covered
• 0181U - Red cell antigen (Colton blood group) genotyping (CO), gene analysis, AQP1 (aquaporin 1 [Colton blood group]) exon 1 - Not Covered
• 0182U - Red cell antigen (Cromer blood group) genotyping (CROM), gene analysis, CD55 (CD55 molecule [Cromer blood group]) exons 1-10 - Not Covered
• 0183U - Red cell antigen (Diego blood group) genotyping (DI), gene analysis, SLC4A1 (solute carrier family 4 member 1 [Diego blood group]) exon 19 - Not Covered
• 0184U - Red cell antigen (Dombrock blood group) genotyping (DO), gene analysis, ART4 (ADP-ribosyltransferase 4 [Dombrock blood group]) exon 20 - Not Covered

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• 0185U - Red cell antigen (H blood group) genotyping (FUT1), gene analysis, FUT1 (fucosyltransferase 1 [H blood group]) exon 4 - Not Covered
• 0186U - Red cell antigen (H blood group) genotyping (FUT2), gene analysis, FUT2 (fucosyltransferase 2) exon 2 - Not Covered
• 0187U - Red cell antigen (Duffy blood group) genotyping (FY), gene analysis, ACKR1 (atypical chemokine receptor 1 [Duffy blood group]) exons 1-2 - Not Covered
• 0188U - Red cell antigen (Gerbich blood group) genotyping (GE), gene analysis, GYPC (glycophorin C [Gerbich blood group]) exons 1-4 - Not Covered
• 0189U - Red cell antigen (MNS blood group) genotyping (GYPA), gene analysis, GYPA (glycophorin A [MNS blood group]) introns 1, 5, exon 2 - Not Covered
• 0190U - Red cell antigen (MNS blood group) genotyping (GYPB), gene analysis, GYPB (glycophorin B [MNS blood group]) introns 1, 5, pseudoexon 3 - Not Covered
• 0191U - Red cell antigen (Indian blood group) genotyping (IN), gene analysis, CD44 (CD44 molecule [Indian blood group]) exons 2, 3, 6 - Not Covered
• 0192U - Red cell antigen (Kidd blood group) genotyping (JK), gene analysis, SLC14A1 (solute carrier family 14 member 1 [Kidd blood group]) gene promoter, exon 9 - Not Covered
• 0193U - Red cell antigen (JR blood group) genotyping (JR), gene analysis, ABCG2 (ATP binding cassette subfamily G member 2 [Junior blood group]) exons 2-26 - Not Covered
• 0194U - Red cell antigen (Kell blood group) genotyping (KEL), gene analysis, KEL (Kell metallo-endopeptidase [Kell blood group]) exon 8 - Not Covered
• 0195U - KLF1 (Kruppel-like factor 1), targeted sequencing (ie, exon 13) - Not Covered

Red cell antigen (Lutheran blood group) genotyping (LU), gene analysis, BCAM (basal cell adhesion molecule [Lutheran blood group]) exon 3

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CPT® Code(s)

Description

Comments

• 0197U - Red cell antigen (Landsteiner-Wiener blood group) genotyping (LW), gene analysis, ICAM4 (intercellular adhesion molecule 4 [Landsteiner-Wiener blood group]) exon 1 - Not Covered
• 0198U - Red cell antigen (RH blood group) genotyping (RHD and RHCE), gene analysis Sanger/chain termination/conventional sequencing, RHD (Rh blood group D antigen) exons 1-10 and RHCE (Rh blood group CcEe antigens) exon 5 - Not Covered
• 0199U - Red cell antigen (Scianna blood group) genotyping (SC), gene analysis, ERMAP (erythroblast membrane associated protein [Scianna blood group]) exons 4, 12 - Not Covered
• 0200U - Red cell antigen (Kx blood group) genotyping (XK), gene analysis, XK (X-linked Kx blood group) exons 1-3 - Not Covered
• 0201U - Red cell antigen (Yt blood group) genotyping (YT), gene analysis, ACHE (acetylcholinesterase [Cartwright blood group]) exon 2 - Not Covered
• 0221U - Red cell antigen (ABO blood group) genotyping (ABO), gene analysis, next-generation sequencing, ABO (ABO, alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase) gene - Not Covered
• 0222U - Red cell antigen (RH blood group) genotyping (RHD and RHCE), gene analysis, next-generation sequencing, RH proximal promoter, exons 1-10, portions of introns 2-3 - Not Covered
• 0246U - Red blood cell antigen typing, DNA, genotyping of at least 16 blood groups with phenotype prediction of at least 51 red blood cell antigens - Not Covered
• 0268U - Hematology (atypical hemolytic uremic syndrome [aHUS]), genomic sequence analysis of 15 genes, blood, buccal swab, or amniotic fluid - Not Covered
• 0269U - Hematology (autosomal dominant congenital thrombocytopenia), genomic sequence analysis of 14 genes, blood, buccal swab, or amniotic fluid - Not Covered

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Genetic and Coagulation Testing for Noncancer Blood Disorders

• Effective Date: 07/07/2023
• Revision Date: 07/07/2023
• Review Date: 07/07/2023
• Policy Number: HUM-0525-017
• Page: 20 of 29

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Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

0282U

Red blood cell antigen typing, DNA, genotyping of 12 blood group system genes to predict 44 red blood cell antigen phenotypes

Not Covered

0283U

von Willebrand factor (VWF), type 2B, platelet-binding: evaluation, radioimmunoassay, plasma

Not Covered

0284U

von Willebrand factor (VWF), type 2N, factor VIII and VWF binding evaluation, enzyme-linked immunosorbent assays (ELISA), plasma

Not Covered

0303U

Hematology, red blood cell (RBC) adhesion to endothelial/subendothelial adhesion molecules, functional assessment, whole blood, with algorithmic analysis and result reported as an RBC adhesion index; hypoxic

Not Covered

0304U

endothelial/subendothelial adhesion molecules, functional assessment, whole blood, with algorithmic analysis and result reported as an RBC adhesion index; normoxic Hematology, red blood cell (RBC) functionality and deformity as

Not Covered

0305U CPT®

a function of shear stress, whole blood, reported as a maximum elongation index

Not Covered

Category Ill Code(s)

Description

Comments

No code(s) identified

HCPCS Code(s)

Description Genetic counseling, under physician supervision, each 15

Comments

References

1. American College of Medical Genetics and Genomics (ACMG). Venous thromboembolism laboratory testing (factor V Leiden and factor II c.*97G>A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). https://www.acmg.net. Published December 2018. Accessed July 13, 2023.
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3. Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.
4. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin. Hemoglobinopathies in pregnancy. https://www.acog.org. Published January 2007. Updated 2021. Accessed July 13, 2023.
5. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin. Inherited thrombophilias in pregnancy. https://www.acog.org. Published July 2018. Updated 2022. Accessed July 13, 2023.
6. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin. Prevention of Rh D alloimmunization. https://www.acog.org. Published August 2017. Updated 2021. Accessed July 13, 2023.
7. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin. Thrombocytopenia in pregnancy. https://www.acog.org. Published March 2019. Updated 2022. Accessed July 13, 2023.
8. ClinicalKey. Clinical Overview. Sickle cell disease. https://www.clinicalkey.com. Updated June 22, 2023. Accessed July 9, 2023.
9. ClinicalKey. Clinical Overview. Thalassemia. https://www.clinicalkey.com. Updated April 13, 2023. Accessed July 9, 2023.
10. ECRI Institute. ECRIgene Genetic Test Hotline Response. Genetic testing for atypical hemolytic uremic syndrome. https://www.ecri.org. Published December 2018. Accessed July 8, 2023.
11. ECRI Institute. Genetic Test Assessment. ID CORE XT genotyping test (Progenika Biopharma S.A., a Grifols Co.) for assessing blood donor-recipient compatibility. https://www.ecri.org. Published July 2020. Accessed July 8, 2023.
12. Fasano RM, Chou ST. Red blood cell antigen genotyping for sickle cell disease, thalassemia, and other transfusion complications. Transfus Med Rev. 2016;30(4):197-201. Accessed July 9, 2023.

References

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28. MCG Health. Hemoglobin C and E – HBB Gene. 27th edition. https://www.mcg.com. Accessed July 9, 2023.
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    Genetic and Coagulation Testing for Noncancer Blood Disorders
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    Revision Date: 07/07/2023
    Review Date: 07/07/2023
    Policy Number: HUM-0525-017
    Page: 24 of 29

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31. MCG Health. Von Willebrand disease – VWF gene. 27th edition. https://www.mcg.com. Accessed July 9, 2023.
32. Merck Manual: Professional Version. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. https://www.merckmanuals.com. Updated June 2022. Accessed August 2, 2022.
33. Merck Manual: Professional Version. Overview of platelet disorders. https://www.merckmanuals.com. Updated June 2022. Accessed August 2, 2022.
34. Merck Manual: Professional Version. Sickle cell disease. https://www.merckmanuals.com. Updated June 2022. Assessed August 2, 2022.
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36. National Center for Biotechnology Information (NCBI). Genetic Testing Registry. Beta-thalassemia. https://www.ncbi.nlm.nih.gov. Published September 28, 2000. Updated February 4, 2021. Accessed July 13, 2023.
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47. UpToDate, Inc. Acute vaso-occlusive pain management in sickle cell disease.

47. UpToDate, Inc. Antithrombin deficiency. https://www.uptodate.com. Updated June 2023. Accessed July 9, 2023.
48. UpToDate, Inc. Clinical presentation and diagnosis of heparin-induced thrombocytopenia. https://www.uptodate.com. Updated June 2023. Accessed July 9, 2023.
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Review Date: 07/07/2023
Policy Number: HUM-0525-017
Page: 26 of 29

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50. UpToDate, Inc. Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. https://www.uptodate.com. Updated June 2023. Accessed July 9, 2023.
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Revision Date: 07/07/2023
Review Date: 07/07/2023
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Review Date: 07/07/2023
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Appendix A Pre- and Post-Test Genetic Counseling Criteria

Pre- and post-test genetic counseling performed by any of the following qualified medical professionals:

• Genetic counselor who is board-certified or board-eligible by the American Board of Medical Genetics and Genomics (ABMGG) or American Board of Genetic Counseling, Inc (ABGC) and is not employed by a commercial genetic testing laboratory;
• Genetic clinical nurse (GCN) or advanced practice nurse in genetics (APNG) who is credentialed by the Genetic Nursing Credentialing Commission (GNCC) or the American of Nurses Credentialing Center (ANCC) and is not employed by a commercial genetic testing laboratory;
• Medical geneticist who is board-certified or board-eligible by ABMGG;
• Treating physician who has evaluated the individual to be tested and has completed a family history of three generations

Appendix B Family Relationships

Degree of Relationship:

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