Local Coverage Determination (LCD)

MolDX: Genetic Testing for Hypercoagulability/Thrombophilia (Factor V Leiden, Factor II Prothrombin, and MTHFR)

L36400

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Source LCD ID
N/A
LCD ID
L36400
Original ICD-9 LCD ID
Not Applicable
LCD Title
MolDX: Genetic Testing for Hypercoagulability/Thrombophilia (Factor V Leiden, Factor II Prothrombin, and MTHFR)
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL36400
Original Effective Date
For services performed on or after 04/16/2016
Revision Effective Date
For services performed on or after 07/20/2023
Revision Ending Date
N/A
Retirement Date
N/A
Notice Period Start Date
03/01/2016
Notice Period End Date
04/15/2016
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Issue

Issue Description

This LCD outlines noncoverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity.

Issue - Explanation of Change Between Proposed LCD and Final LCD

CMS National Coverage Policy

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

42 CFR §410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS internet-Only Manual Pub 100-02 Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This is a non-coverage policy for genetic testing for thrombophilia testing for the Factor V Leiden (FVL) variant in F5 gene, the 20210G>(G20210A) variant in the F2 gene, and the MTHFR gene which encodes the 5, 10-methylenetetrahydrofolate reductase enzyme. Genetic testing for these genes for all risk factors, signs, symptoms, diseases, or conditions, including cardiovascular risk assessment, are non -covered except for pregnant patients.

Testing for FVL and F2 G20210A mutations is indicated for pregnant patients who have a history of personal venous thromboembolism (VTE) associated with a non-recurrent (transient) risk factor who are not otherwise receiving anticoagulant prophylaxis. The results of genetic testing can inform risk stratification for VTE recurrence and subsequent need for antenatal prophylaxis. However, Medicare will not add coverage of thrombophilia testing for pregnant women because they likely represent a very small group of potential Medicare (disabled) patients. Claims submitted on this limited Medicare population will deny per the policy, but should be appealed for coverage with submission of medical records supporting the necessity for testing, and specify how testing changed anticoagulant prophylaxis management for the patient.

Background
Thrombophilia (or hypercoagulability) is the propensity to develop thrombosis due to either an acquired or inherited defect in the coagulation system. The major clinical manifestation of thrombophilia is VTE. Acquired thrombophilia risk factors include but are not limited to advancing age (> 50), trauma, malignancy, chemotherapy, major surgery, immobilization, pregnancy, estrogen, inflammation, antiphospholipid antibody syndrome, myeloproliferative disorders, heparin-induced thrombocytopenia, liver disease, nephrotic syndrome and prolonged air travel. Inherited thrombophilia risk factors include deficiencies in antithrombin, Protein C, Protein S, mutation in FVL and F2, and dysfibrinogenemias. Mixed or unknown risk factors include hyperhomocysteinemia, elevated levels of Factor VIII, acquired Protein C resistance in the absence of Factor V Leiden, and elevated levels of Factors IX and XI.

Testing for thrombophilia may consist of functional testing, antigenic testing, and genetic testing.
Functional testing for thrombophilia may include tests such as:

  • Anti-phospholipid antibody (lupus anticoagulant)
  • Protein C
  • Protein S
  • Activated Protein C resistance (a surrogate for Factor V Leiden mutation)
  • Factor VIII
  • Fibrinogen
  • C-reactive protein
  • Homocysteine levels

Antigenic testing may be performed to identify specific glycoprotein antibodies associated with abnormal functional anti-phospholipid antibody studies, or to subtype deficiencies detected by decreased Protein S, Protein C and Antithrombin functional activity.

VTE is characteristically seen in deficiencies in Protein C, Protein S and antithrombin, as well as with Factor V Leiden (FVL) and F2 mutations. This is unlike the combination of arterial and venous thrombosis associated with hyperhomocysteinemia and lupus anticoagulant.

Genetic Testing for Thrombophilia
Genetic testing is available for a number of types of inherited thrombophilia, including mutations in the FVL, F2 and the MTHFR genes. However, the clinical utility of testing is uncertain. The clinical utility of genetic testing depends on the ability of testing results to change management that results in improved clinical outcomes. The clinical utility of genetic testing for thrombophilia is based on the overall risk of thromboembolism and the risk/benefit ratio of treatment, primarily with anticoagulants.

During the previous 5 years, a number of guidelines and/or position statements on testing for thrombophilia have been published. In 2011, The Evaluation of Genomic Applications in Practice and Prevention Working Groups (EGAPP) addressed genetic testing for FVL and F2 mutations. The expert consensus recommended:

  • There is no evidence that knowledge of FVL/F2 mutation status in patients with VTE affects anticoagulation treatment to avoid recurrence;
  • There is convincing evidence that anticoagulation beyond three months reduces recurrence of VTE, regardless of mutation status;
  • There is no evidence that knowledge of FVL/F2 mutation status among symptomatic family members of patients with VTE leads to anticoagulation aimed at avoiding initial episodes of VTE (See note).

Note: The Medicare benefit applies only to individuals with signs and symptoms of disease. There is no Medicare benefit for assessment of thrombosis risk in asymptomatic patients (aka screening for inherited thrombophilia) or in asymptomatic individuals whose relatives have documented inherited thrombophilia.

In 2008, the American College of Chest Physician’s (ACCP) published guidelines for the treatment of thromboembolic disease stated the following concerning genetic testing for thrombophilia:

  • The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinates of the risk of recurrence.

In the 2012, ACCP Clinical Practice Guidelines, Guyatt10 and Bates3 make the following recommendations for treatment and management of VTE:

  • In persons with asymptomatic thrombophilia (i.e., without a previous history of VTE), we recommend against the long ­term daily use of mechanical or pharmacologic thromboprophylaxis to prevent VTE;
  • For pregnant women with no prior history of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and have a positive family history for VTE, we suggest antepartum prophylaxis with prophylactic­ or intermediate­ dose low­ molecular weight heparin (LMWH) and postpartum prophylaxis for 6 weeks with prophylactic­ or intermediate dose LMWH or vitamin K antagonists (VKAs) targeted at INR 2.0 to 3.0 rather than no prophylaxis;
  • For all pregnant women with prior VTE, we suggest postpartum prophylaxis for 6 weeks with prophylactic­ or intermediate­ dose LMWH or VKAs targeted at INR 2.0 to 3.0 rather than no prophylaxis;
  • For pregnant women at low risk of recurrent VTE (single episode of VTE associated with a transient risk factor not related to pregnancy or use of estrogen), we suggest clinical vigilance antepartum rather than antepartum prophylaxis;
  • For pregnant women at moderate to high risk of recurrent VTE (single unprovoked VTE, pregnancy­ or estrogen-­related VTE, or multiple prior unprovoked VTE not receiving long ­term anticoagulation), we suggest antepartum prophylaxis with prophylactic­ or intermediate-­dose LMWH rather than clinical vigilance or routine care.

In the 2013, American Congress of Obstetricians and Gynecologists (ACOG) clinical management guidelines for inherited thrombophilia in pregnancy, ACOG experts note that the following guidelines are based on limited or inconsistent scientific evidence:

“Screening for thrombophilia is controversial. It is useful only when results will affect management decisions, and it is not useful in situations where treatment is indicated for other risk factors.
Screening may be considered in the following clinical settings:

  • A personal history of VTE that was associated with a non-recurrent risk factor (eg, fractures, surgery, and prolonged immobilizations).
  • A first-degree relative (e.g., parent or sibling) with a history of high-risk thrombophilia.” (See ACOG note below)

ACOG also stated that testing for inherited thrombophilia in women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear if anticoagulation therapy reduces recurrence. They indicate that there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or LMWH prevents recurrence in these patients and note insufficient evidence to either screen for or treat women with inherited thrombophilia including complications such as fetal growth restriction or preeclampsia.

On behalf of the American College of Medical Genetics (ACMG) Grody7 recommended testing for FVL for the following indications:

  • Age under 50, any venous thrombosis;
  • Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins);
  • Recurrent venous thrombosis;
  • Venous thrombosis and a strong family history of thrombotic disease;
  • Venous thrombosis in pregnant women or women taking oral contraceptives;
  • Relatives of individuals with venous thrombosis under age 50;
  • Myocardial infarction in female smokers under age 50.

ACMG suggested that FVL testing may also be considered in the following situations:

  • Venous thrombosis, age over 50, except when active malignancy is present;
  • Relatives of individuals known to have FVL. Knowledge that they have the FVL mutation may influence management of pregnancy and may be a factor in decision­making regarding oral contraceptive use;
  • Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth. Knowledge of FVL carrier status may influence management of future pregnancies.

FVL testing is not recommended for the following:

  • A general population screen;
  • A routine initial test during pregnancy or prior to the use of oral contraceptives, hormone replacement therapy (HRT) or selective estrogen receptor modulators (SERMs);
  • A prenatal or newborn test, or as a routine test in asymptomatic children;
  • A routine initial test in individuals with arterial thrombosis (testing may be considered, however, in selected young individuals [under age 50] with unexplained arterial thrombosis in the absence of other risk factors for atherosclerotic vascular disease).

In 2013, (ACMG) published a practice guideline on the lack of evidence for MTHFR polymorphism testing. Among a number of recommendations, ACMG experts concluded:

  • MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss;
  • MTHFR polymorphism genotyping should not be ordered for at-risk family members.

Non-coverage Summary
Genetic testing for inherited thrombophilias is controversial. While the association between FVL and F2 mutations and increased risk for VTE is apparent, the actual impact of this increased risk on clinical management is less certain. Older professional society guidelines recommend genetic testing for thrombophilia for a wide range of indications, while more recent consensus statements and recommendations suggest much more limited clinical utility of testing.

The population for which genetic testing results have direct implications for treatment is pregnant women with a previous history of VTE associated with a transient risk factor (e.g., surgery, trauma). These women would typically not be treated with antepartum anticoagulant prophylaxis unless they were found to have a genotype associated with a high risk of VTE recurrence (FVL homozygosity, F2 G20210A homozygosity, or compound heterozygosity for FVL and F2 G20210A). Genetic testing for these patients is indicated.

There may also be benefit to screening pregnant women with a family history of known thrombophilia, as those women found to have a high-risk genotype would be offered antenatal prophylactic anticoagulant therapy even in the absence of a personal history of VTE. However, the Medicare benefit applies only to patients with signs and symptoms of disease and does not include screening in asymptomatic patients.

Finally, despite many earlier publications suggesting a link between MTHFR polymorphisms and a risk for a wide spectrum of obstetric and cardiovascular complications, it is now accepted that MTHFR genotype alone is not associated with VTE. There is no clinical indication for MTHFR genotyping in any population.

There is insufficient evidence in the published peer-reviewed scientific literature to support coverage for genetic testing for inherited thrombophilias outside the pregnant women as described above. Genetic testing for FVL and F2 G20210A is considered investigational for all other indications. However, Medicare may consider coverage for FVL and/or F2 genetic testing in unusual circumstances where testing will change clinical management of the patient. Denied claims can be appealed with supporting evidence of specific medical necessity. Only providers with evidence of formal training with board eligibility or certification in hematology/oncology, hematopathology or coagulation disorders at an accredited program satisfy reasonable and necessary criteria for these tests. There is broad consensus in the medical literature that MTHFR genotyping has no clinical utility in any clinical scenario. This testing is considered investigational and is NOT a Medicare benefit.

Summary of Evidence

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Analysis of Evidence (Rationale for Determination)

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Proposed Process Information

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This request was MAC initiated.
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Coding Information

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Group 1

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ICD-10-CM Codes that DO NOT Support Medical Necessity

Group 1

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Documentation Requirements
The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See “Coverage Indications, Limitations, and/or Medical Necessity"). This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

Documentation supporting the medical necessity should be legible, maintained in the patient's medical record, and must be made available to the MAC Contractor upon request.

Sources of Information

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Bibliography
  1. American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122(3):706-717.
  2. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220.
  3. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S.
  4. Bauer KA, Lip GYH. Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors. In: Leung LLK, ed. UptoDate. UptoDate; 2011. Accessed June 12, 2023. www.uptodate.com
  5. Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med. 2012;14:39-50.
  6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S.
  7. Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA; ACMG Factor V. Leiden Working Group. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3(2):139-148.
  8. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009;102(2):360-370.
  9. Grandone E, Villani M, Tiscia GL, et al. Clinical pregnancies and live births in women approaching ART: a follow-up analysis of 157 women after thrombophilia screening. Thromb Res. 2014;133(2):168-172.
  10. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):7S-47S.
  11. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR. Genet Med. 2013;15(2):153-156.
  12. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112(12):4432-4436.
  13. Lijfering WM, Brouwer JL, Veeger NJ, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009;113(21):5314-5322.

Revision History Information

Revision History Date Revision History Number Revision History Explanation Reasons for Change
07/20/2023 R7

Posted 07/27/2023: Under CMS National Coverage Policy updated section heading for 2nd regulation, and revised the following regulation CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests to include section 80.1.1. Under Bibliography changes were made to citations to reflect AMA citation guidelines. Formatting, punctuation, and typographical errors were corrected throughout the LCD. This revision is effective on 7/20/2023.

  • Other (Review)
08/12/2021 R6

08/12/2021-Under Bibliography changes were made to citations to reflect AMA citation guidelines. Formatting, punctuation, and typographical errors were corrected throughout the LCD. Review completed 06/23/2021.

  • Other (Review)
11/01/2019 R5

Change Request 10901 Local Coverage Determinations (LCDs): it will no longer be appropriate to include Current Procedure Terminology (CPT)/Health Care Procedure Coding System (HCPCS) codes or International Classification of Diseases Tenth Revision-Clinical Modification (ICD-10-CM) codes in the LCDs. All CPT/HCPCS, ICD-10 codes, and Billing and Coding Guidelines have been removed from this LCD and placed in the Billing and Coding Article related to this LCD. Consistent with Change Request 10901, if any language from IOMs and/or regulations was present in the LCD, it has been removed and the applicable manual/regulation has been referenced.

  • Other (compliance with CR 10901)
01/01/2019 R4

01/01/2019-Code update: description change 81240 & 81291. Annual review completed 12/03/2018. Numbered the bibliography.

  • Revisions Due To CPT/HCPCS Code Changes
02/01/2018 R3

02/01/2018- Annual review completed 01/11/2018.  At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Other (-Annual Review

    )
03/01/2017 R2 03/01/2017- Annual review completed 02/02/2017- minor formatting changes & added MolDX to title & changed contractor Determination number from Path-041 to to MolDX-001.
  • Other (Annual Review)
04/16/2016 R1 06/01/2016-Clarification, replaced prothrombin (F2) and Prothrombin (PT) gene with F2 gene throughout the policy. Added the following under non-coverage summary: However, Medicare may consider coverage for FVL and/or F2 genetic testing in unusual circumstances where testing will change clinical management of the patient. Denied claims can be appealed with supporting evidence of specific medical necessity. Only providers with evidence of formal training with board eligibility or certification in hematology/oncology, hematopathology or coagulation disorders at an accredited program satisfy reasonable and necessary criteria for these tests. Updated sources of information section.
  • Other (Other-clarification)
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