LCD L40259: MolDX: Genetic Testing for Hereditary Thrombophilia

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 requirements are met:

• The patient:

• Presents with venous thromboembolism (VTE) that is associated with non-surgical major transient or hormonal risk factors (as defined in American Society of Hematology (ASH) guidelines), OR

• Presents with cerebral or splanchnic venous thrombosis, in settings where short term primary treatment is the standard of care and testing will inform the decision for long-term anticoagulation (when anticoagulation would otherwise be discontinued); OR

• Currently carries a diagnosis of cancer and ALL of the following:

• is receiving systemic therapy in the ambulatory setting AND

• meets the clinical criteria for low or intermediate VTE risk as determined by a validated risk assessment tool recognized by national or international oncology consensus guidelines (e.g., ASH) AND

• has a family history of VTE in first degree relative (s).

• Genetic testing will guide clinical management relevant to VTE (e.g., initiation or duration of anticoagulation).

• The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence (e.g. as determined by ASH) 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 (i.e., a known familial variant).

• The test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility.

• The patient must not have been previously tested by the same or similar test for the same indication and genetic content, and testing must conform to all other applicable policy (e.g. provisions of repeat germline testing as defined in L38274).

• 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 VTE 11 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 has established 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, anticardiolipin 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