MolDX: Genetic Testing for Hereditary Thrombophilia

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary.

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

This policy defines coverage for Lab-Developed Tests (LDTs), Federal Drug Administration (FDA)-cleared, and FDA-approved clinical laboratory tests for hereditary thrombophilia including Next Generation Sequencing (NGS) tests. This policy’s scope is specific for hereditary germline testing.

Criteria for Coverage

Genetic testing for hereditary thrombophilia is covered when ALL of the following are met:

1. The patient presents with venous thromboembolism (VTE) and at least one of the following is true:
1. The patient presents with VTE that is associated with non-surgical major transient or hormonal risk factors (as defined in American Society of Hematology (ASH) guidelines), OR
2. The patient presents with cerebral or splanchnic venous thrombosis, in settings where short term primary treatment is the standard of care (settings where anticoagulation would otherwise be discontinued) and testing will inform the decision for long-term anticoagulation.
2. Genetic testing will guide VTE clinical management (e.g., duration of anticoagulation).
3. The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence (as determined by American Society of Hematology) required for clinical decision making for its intended use that can be reasonably detected by the test. A single variant may be tested if it is the only variant considered to be reasonable and necessary for a patient given that it is a known familial variant.
4. The test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that there could be reasonable expectation of misutilization by the patient or treating physician, resulting in impaired patient outcomes.
5. The testing does not conflict with other applicable policy, specifically provisions of repeat germline testing defined in L38288.
6. The test has satisfactorily completed a Technical Assessment (TA) by Molecular Diagnostic Services Program (MolDX^®).

Venous thromboembolism (VTE) is characterized by the formation of venous thrombi and is inclusive of deep vein thrombosis (DVT), which in turn increases the risk of pulmonary embolism (PE), a life-threatening complication.¹ VTE occurs with an incidence of approximately 1 to 1.5 per 1000 person-years, with an absolute lifetime risk of approximately 8-11%.^2-6 It is the third most common cause of death worldwide.⁷ The risk of VTE increases with age, being approximately 1 in 10,000 persons per year in those under age 40 and increasing to 1 in 100 persons per year in those over age 75.^2,8 Following first incidence, recurrence risk is greatest within the first 6 to 12 months post-VTE.⁹ The 5-year risk of VTE recurrence is estimated at approximately 20%, while the 10-year risk is estimated at approximately 30%.^2,9,10 Causality of VTE is often multifactorial, due to the interaction of a wide range of acquired and inherited risk factors, most of which span Virchow’s triad, which consists of stasis of blood flow, hypercoagulability, and endothelial injury.^1,7

A significant proportion of patients with venous thromboembolism have an acquired or inherited thrombophilia.¹¹ This is defined as one of several conditions that render a given individual at a higher-than-normal risk for VTE¹¹ and include the acquired antiphospholipid syndrome (APS) as well as hereditary thrombophilias such as gain of function mutations in factor V (factor V Leiden, FVL) and factor II c.*97G>A (also known as prothrombin 20210G>A, PGM), deficiencies of antithrombin (AT), protein C (PC), and protein S (PS).^2,11 Testing for inherited and acquired thrombophilia is often conducted in patients with VTE, particularly in those who present with VTE at a young age, experience recurrent VTE, have thrombosis at unusual sites, or have a family history of thrombophilia.¹¹ The proportion of variance attributed to genetic effects in VTE is estimated to be as high as 60%¹² and there is a moderate to high chance of discovering thrombophilia when testing patients with VTE or relatives of patients with VTE and thrombophilia.¹¹ Approximately 25% of unselected cases of VTE have a known genetic factor, with the rate increasing to 63% of familial cases.² Nevertheless, knowledge of hereditary thrombophilia status does not meaningfully impact patient management in the setting of acute thrombosis and the incremental clinical value of knowing about the presence or absence of thrombophilia may be low in many settings, such that the risks associated with testing may outweigh potential benefits.¹³ Thrombophilia testing can lead to overdiagnosis, wherein patients are labeled with a disease or abnormal condition that would not have caused clinical harm if left undiscovered. As an unintended result, there may be physical, psychological, or financial harm to patients due to discovery of this condition.¹¹ As an example, patients may be inappropriately treated with anticoagulation, resulting in an increased risk of bleeding.

The American Society of Hematology set out to establish evidence-based recommendations with respect to the clinical utility of thrombophilia testing in defined clinical scenarios, published as the 2023 Guidelines for Management of Venous Thromboembolism: Thrombophilia Testing (2023 ASH Thrombophilia Testing Guidelines).¹¹ The guidelines evaluated the clinical utility of conducting a thrombophilia testing panel to aid in clinical decision-making across 23 clinical scenarios. The thrombophilia testing panel described in the guidelines consists of FVL, PGM, and deficiencies of protein S, protein C and antithrombin, along with testing for acquired APS by assessment for lupus anticoagulant, andicardiolipin antibodies, and anti-beta-2 glycoprotein 1 antibodies.¹¹ These are considered to be rational components of a thrombophilia panel due to consistent and reproducible VTE association.¹¹

FVL and PGM both result from a single nucleotide change and are easily identified by genetic testing.² The FVL mutation renders factor V resistant to cleavage by activated protein C (APC) and therefore prolongs its procoagulant activity. Genetic testing for FVL can be conducted as the primary diagnostic test or it can follow a positive result from a functional APC assay. PGM is a gain-of-function point mutation that leads to increased levels of prothrombin and prothrombin activity. Due to significant overlap with the upper limit of normal prothrombin levels, PGM must be identified through genetic testing. Finally, a myriad of pathogenic variants have been described in genes encoding protein C (PROC), protein S (PROS1), and antithrombin (SERPINC1); therefore, testing for these inherited thrombophilias is usually functional and involves assessment of activity or in some cases, antigen level.⁹

Heterozygosity for FVL is the most common inherited thrombophilia in the United States with a prevalence of approximately 3-7%.^14,15 In a population set from the United States Physicians' Health Study and the Women's Health Study, the prevalence of FVL heterozygosity was 5.3% of White Americans, 2.2% of Hispanic Americans, 1.2% of Native Americans, 1.2% of African Americans, and 0.45% of Asian Americans.¹⁶ FVL is the most common inherited thrombophilia identified in individuals with VTE, with a prevalence of 10% to 20% in the VTE population.¹⁴ The lifetime risk of VTE increases 7-fold for FVL heterozygotes and approximately 20-fold for homozygotes.¹⁴ Nevertheless, there is no clinical evidence that heterozygosity of factor V Leiden increases overall mortality and most people who carry the mutation will never develop VTE.¹⁴ PGM is the second most common thrombophilia, with a prevalence of 1-6% in individuals with European ancestry, 0.5% in African Americans, and very rare occurrence in Asians, Africans, and Native Americans.^17,18 The prevalence is approximately 6% in persons with VTE.^19,20 Heterozygosity for PGM increases the risk of first VTE by 2-3 times over baseline and homozygosity further increases risk.¹⁸ However, as with FVL, most individuals with PGM will not develop VTE.^20,21 Protein C, Protein S, and antithrombin deficiency are rare in the United States with a prevalence between 0.02-0.7% for each deficiency in the general population and 1-3% in those with VTE. The relative risk of VTE is 5-10 times over baseline.^{9, 22-24} Notably, the prevalence of Protein C, Protein S, and antithrombin deficiency are significantly higher in the East Asian population of persons with VTE, being 3.8-7.1%.²⁵ In addition, the possibility of homozygosity and double heterozygosity for FVL and PGM along with rare and complex genotype combinations have been described and merit consideration, as they carry increased risk.^26-29 Notably, FVL homozygosity is found in approximately 1% of initial isolated cases of VTE and 6-12% of FVL heterozygotes also harbor the PGM.²

Additional tests that are sometimes included as components of a thrombophilia panel were not considered in ASH guidelines development, as they have not sufficiently demonstrated association with VTE. These include methylenetetrahydrofolate reductase [MTHFR] polymorphisms 677C>T, 1298A>C, as well as other tests that have not conclusively demonstrated association with VTE, such as factor VIII, factor IX and factor XI activity, plasminogen activator inhibitor type 1 (PAI-1), and the 4G/5G PAI-1 promoter polymorphism).^11,30 The ASH Thrombophilia Testing Guidelines considered the effect of panel testing for all 23 clinical scenarios, whereas selective thrombophilia testing for a single thrombophilia type was only considered in the setting of a known familial thrombophilia.¹¹

For each clinical scenario, the ASH Guidelines panel weighed the benefits and harms of either thrombophilia testing and indefinite anticoagulation of only thrombophilia-positive individuals vs no thrombophilia testing with indefinite anticoagulation for all or none, dependent on standard of care in accordance with other ASH VTE guidelines.¹¹ Additional clinical scenarios considered thromboprophylaxis during risk episodes for VTE and avoidance of hormone treatment dependent on thrombophilia status.¹¹ Since these clinical questions have not been directly addressed by randomized controlled trials (RCT), guidelines recommendations were based on modelling wherein prevalence and risk association data were used to calculate the absolute risk of events in people with and without thrombophilia using a previously published approach.^11,31 The juxtaposition of testing vs. not testing for thrombophilia balanced the risk for VTE and bleeding events, cost and burden associated with both testing and anticoagulation treatment or thromboprophylaxis, as well as patient preferences, with a threshold-based approach to judging the effect size of outcomes. For each guideline question, the McMaster GRADE Centre prepared a GRADE Evidence to Decision (EtD) framework, using the GRADEpro Guideline Development Tool (www.gradepro.org).^11,32,33

Based on the framework described above, modeling data and risk-benefit considerations resulted in recommendations against thrombophilia testing for most clinical scenarios. The evidence supported conditional recommendations for thrombophilia testing in limited clinical scenarios, which are described below.

The risks and benefits of thrombophilia testing were considered in the decision of whether to use testing to guide the duration of anticoagulation in patients who have completed short-term anticoagulation treatment following VTE provoked by a non-surgical major transient risk factor or hormone use. According to the American Society of Hematology 2020 Guidelines for Management of Venous Thromboembolism: Treatment of Deep Vein Thrombosis and Pulmonary Embolism (ASH VTE Treatment Guidelines), most patients in these categories would stop anticoagulation following short-term treatment.³⁴ With thrombophilia testing, indefinite anticoagulation would be suggested for those with thrombophilia to prevent VTE recurrence (secondary prevention), whereas cessation of treatment would be recommended for those without thrombophilia. Non-surgical major transient risk factors (i.e., risk factors that resolve or can be discontinued after they have provoked VTE) are congruent with those outlined in the ASH VTE Treatment Guidelines and include confinement to a hospital bed for at least three days with an acute illness (“bathroom privileges only”), or a combination of minor transient risk factors such as admission to hospital for less than 3 days with an acute illness, confinement to bed out of hospital for at least 3 days with an acute illness, or leg injury associated with decreased mobility for at least 3 days; hormonal risk factors include estrogen therapy (e.g. oral contraceptives, hormone replacement therapy), pregnancy and puerperium.^11,34

A GRADE EtD framework was prepared to weigh the risks and benefits of thrombophilia testing for each clinical scenario and can be accessed through the ASH Database of GRADE EtD’s and Guidelines. A summary of the evidence is presented below, weighing the benefit of reduction in VTE recurrence vs an increase in major bleeds following thrombophilia testing. The estimate for VTE recurrence subsequent to VTE provoked by a non-surgical major transient risk factor, pregnancy or postpartum, or combined oral contraceptives is 50 per 1000 in the first year following acute VTE; this estimate is based on a single systematic review.¹¹ The risk of major bleeding is estimated to be 5 per 1000 patients per year for those with a low baseline risk for bleeding and 15 per 1000 per year for those with high baseline risk of bleeding; this estimate is derived from the highest and lowest observed rates across 11 RCTs.¹¹ The potential benefit of thrombophilia testing in this scenario is reduction in recurrent VTE. Calculations rooted in 24 studies demonstrated that a strategy of testing and indefinite anticoagulation in patients with thrombophilia would lead to 21 fewer VTE recurrences per 1000 patients per year (range of 10-35 fewer). Thirteen of the 21 per 1000 prevented VTE recurrences are expected to be prevented by treatment of patients with FVL or PGM.¹¹ The potential harm in this scenario is the increased risk of major bleeding due to anticoagulation. Calculations derived from data spanning 31 studies demonstrated that this testing and treating strategy would result in 2 additional major bleeds per 1000 patients per year in those at low risk for bleeding (range of 0-7 additional), and 7 more major bleeds per 1000 patients per year in those at high risk of bleeding (range of 1-21 additional).¹¹ Therefore, it was determined that on the balance, the desirable effects of preventing recurrent VTE outweigh the undesirable effects of major bleeding, such that a strategy of testing and treating patients with thrombophilia is favored.¹¹

The guideline panel also evaluated the risks and benefits of thrombophilia testing to guide the duration of anticoagulation in patients with cerebral or splanchnic venous thrombosis (in the absence of liver cirrhosis) who have completed primary treatment with short-term anticoagulation in a setting where anticoagulation would be discontinued. Guidelines are indecisive regarding the optimal duration of anticoagulation in these settings, and thrombophilia testing can aid with decision-making.

In patients with cerebral VTE, the risk of recurrence was estimated to be 38 per 1000 in the first year, an estimate based on 4 observational studies.¹¹ The risk of major bleeding was estimated at 5 per 1000 patients per year in those with a low baseline risk of bleeding and 15 per 1000 patients per year in those at high risk of bleeding; this estimate is derived from the lowest and highest observed rates among 11 RCTs. Prevention of VTE recurrence is the benefit of thrombophilia testing in patients with thrombophilia in this setting, as they would indefinitely continue anticoagulation, whereas those without thrombophilia would discontinue treatment. This strategy would result in 18 per 1000 fewer recurrent VTE (range of 14-23 fewer) per year when compared to a no-testing strategy. The potential harm of this strategy is an increase in major bleeding. Calculations based on 15 studies demonstrated that this strategy would result in 3 per 1000 more major bleeds (range of 1-5 additional) per year in patients at baseline low risk for bleeding and 8 per 1000 more major bleeds per year in patients at high risk of bleeding (range of 3-16 additional) per year when compared to a no-testing strategy. Upon balance of risks and benefits, the small desirable effects of preventing recurrent VTE outweigh undesirable effects of more major bleeding, such that a strategy of testing and treating patients with thrombophilia with indefinite anticoagulation and stopping treatment in those negative for thrombophilia is favored.¹¹ Therefore, the ASH Thrombophilia Testing Guidelines panel issued a conditional recommendation for thrombophilia testing and indefinite anticoagulation in VTE patients with cerebral thrombosis with thrombophilia and cessation of anticoagulation in patients without thrombophilia. Testing is not recommended in settings where indefinite anticoagulation is planned.¹¹

In assessment of the risks and benefits of thrombophilia testing of patients with splanchnic venous thrombosis, the overall risk of VTE recurrence was estimated to be 27 per 1000 in the first year, based on two observational studies. The risk of major bleeding was estimated at 5 per 1000 patients per year in those at low baseline risk and 15 per 1000 patients per year in those at high risk of bleeding, derived from lowest and highest observed rates in 11 RCTs.¹¹ Similarly, the benefit of testing in this scenario is reduction in VTE recurrence and the risk of testing and treatment is an increase in major bleeding. Calculations from 18 studies demonstrated that a strategy of testing and indefinite anticoagulation in persons with thrombophilia along with stopping treatment in those without thrombophilia would result in 23 per 1000 fewer recurrent VTE (range of 14-36 fewer) per year compared to a strategy of not testing. Calculations based on 18 studies demonstrated that this strategy would result in 2 per 1000 more major bleeds in low risk patients (range of 1-7 more), and 7 per 1000 more in patients at high risk of bleeding (range of 2-22 additional) compared to a strategy of not testing.¹¹ Therefore, the ASH Thrombophilia Testing Guidelines panel issued a conditional recommendation for thrombophilia testing and indefinite anticoagulation in VTE patients with splanchnic venous thrombosis with thrombophilia and cessation of anticoagulation in patients without thrombophilia. Testing is not recommended in settings where indefinite anticoagulation is planned.¹¹

The ASH Thrombophilia Testing Guidelines further addressed the clinical utility of thrombophilia testing in asymptomatic persons without VTE but with VTE risk factors, such as family history or cancer, for the purpose of decision-making around thromboprophylaxis or hormone use. This indication is not addressed in this policy as testing in asymptomatic individuals is not in scope of Medicare by statute. The modeling approach used to develop these recommendations has limitations in the certainty of evidence as it is based on estimates and calculations in the absence of RCTs directly addressing these clinical questions. Markedly, the guidelines panel did not discuss other conditions associated with thrombophilia such as the JAK2 V617F mutation or paroxysmal nocturnal hemoglobinuria, which are also outside the scope of this policy.¹¹

Additional guideline bodies have also opined on hereditary thrombophilia testing. These include the American College of Obstetricians and Gynecologists (ACOG) which issued clinical management guidelines during pregnancy, applicable to a minority of Medicare patients. Nevertheless, the ACOG Practice Bulletin on Inherited Thrombophilias in Pregnancy reiterates that inherited thrombophilia testing is useful when the results will guide clinical management and is recommended for pregnant individuals with a personal history of VTE with or without a recurrent risk factor as well as in asymptomatic pregnant individuals with family history of a high-risk inherited thrombophilia (indication out of scope of Medicare).³⁵

Notably, MTHFR polymorphisms have been shown not to be associated with venous thromboembolism^30,11 and therefore there is no evidence of clinical utility in testing for these genetic variants in thrombophilia risk assessment. Studies controlling for confounders do not support the relationship between MTHFR polymorphisms and vascular disease^36,37,38 and high levels of homocysteine may be markers of other vascular risk factors.³⁹ Furthermore, multiple clinical trials of folate supplementation for vascular disease reduction showed strongly negative results.^40,41 Large randomized clinical trials found no difference in recurrent thrombotic rates in those with MTHFR polymorphisms randomized to vitamin B supplementation or placebo.^40,42,43 Lack of clinical utility for MTHFR polymorphism testing is supported by guidelines and statements from the American Society of Hematology¹¹ The American College of Medical Genetics⁴⁴ The American College of Obstetricians and Gynecologists,³⁵ and The British Society for Haematology.⁴⁵ Inclusion of MTHFR in testing panels can result in harmful misinterpretation by both patients and physicians.³⁶

Given the abundant literature on hereditary thrombophilia testing and utility in clinical decision-making, this contractor has determined that testing for hereditary thrombophilia may be appropriate to guide clinical management in selected Medicare beneficiaries with VTE.

A thrombophilia testing panel as defined in the ASH Thrombophilia Testing Guidelines is composed of genetic testing for FVL and PGM and functional laboratory testing for PC, PS, AT and acquired APS. The scope of this policy extends to genetic testing only and requires that a given test includes all the relevant genetic information necessary to inform the provider on proper patient management according to established best practices and guidelines. Therefore, a gene panel must contain, at a minimum, all the necessary relevant gene content identified in guidelines at the time of test performance as required for their indicated use to meet clinical utility requirements. Single gene or allele testing is not warranted unless the patient is being evaluated for a known familial variant and therefore a single gene/allele is necessary to confirm the hereditary thrombophilia. Expanded panel content is acceptable when it is relevant, properly validated, with clear and conclusive clinical validity and clinical utility based on published evidence and could not reasonably be mis-utilized by the patient or treating physician to result in impaired patient outcomes. As such, any thrombophilia testing panels that include MTHFR variants will not be covered by this policy. Additional genetic content will be reviewed in the technical assessment process in accordance with the above criteria, noting that at the time of this writing, guidelines maintain that there is insufficient evidence to recommend testing for additional thrombophilias beyond the testing panel described above. Genetic counseling is useful to explain to patients and families the genetic risk and how it is inherited, and to offer psychosocial and ethical guidance.

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34. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
35. ACOG Practice Bulletin No. 197 summary: inherited thrombophilias in pregnancy. Obstet Gynecol. 2018;132(1):249-251. doi:10.1097/AOG.0000000000002705
36. Deloughery TG, Hunt BJ, Barnes GD, Connors JM; WTD Steering Committee. A call to action: MTHFR polymorphisms should not be a part of inherited thrombophilia testing. Res Pract Thromb Haemost. 2022;6(4):e12739. doi:10.1002/rth2.12739
37. Ospina-Romero M, Cannegieter SC, den Heijer M, Doggen CJM, Rosendaal FR, Lijfering WM. Hyperhomocysteinemia and risk of first venous thrombosis: the influence of (unmeasured) confounding factors. Am J Epidemiol. 2018;187(7):1392-1400. doi:10.1093/aje/kwy004
38. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med. 2007;167(5):497-501. doi:10.1001/archinte.167.5.497
39. Rodionov RN, Lentz SR. The homocysteine paradox. Arterioscler Thromb Vasc Biol. 2008;28(6):1031-1033. doi:10.1161/ATVBAHA.108.164830
40. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood. 2007;109(1):139-144. doi:10.1182/blood-2006-04-014654
41. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010;170(18):1622-1631. doi:10.1001/archinternmed.2010.348
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44. Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156. doi:10.1038/gim.2012.165
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• Provider Education/Guidance

• hereditary thrombophilia
• thrombophilia