Venous Thromboembolism
The overall U.S. incidence of venous thromboembolism (VTE) is approximately 1 per 1,000 person-years, and the lifetime clinical prevalence is approximately 5%, accounting for 100,000 deaths annually.[Heit JA, Silverstein MD, Mohr DN, et al. The epide.... ; 86(1): 452-63. PMID 11487036] The risk is strongly age-related, with the greatest risk in older populations. VTE also recurs frequently; estimated cumulative incidence of first VTE recurrence is 30% at 10 years.^1, These figures do not separate patients with known predisposing conditions from those without.

Risk factors for thrombosis include clinical and demographic variables, and at least 1 risk factor can be identified in approximately 80% of patients with thrombosis. The following list includes the most important risk factors:

• Malignancy
• Immobility
• Surgery
• Obesity
• Pregnancy
• Hormonal therapy such as estrogen/progestin or selective estrogen modulator products
• Systemic lupus erythematosus and/or other rheumatologic disorders
• Myeloproliferative disorders
• Liver dysfunction
• Nephrotic syndrome
• Hereditary factors.

Treatment

Treatment of thrombosis involves anticoagulation for a minimum of three to six months. After this initial treatment period, patients deemed to be at a continued high-risk for recurrent thrombosis may continue on anticoagulation therapy for longer periods, sometimes indefinitely. Anticoagulation is effective for reducing subsequent risk of thrombosis but carries its own risk of bleeding.

Inherited Thrombophilia

Inherited thrombophilias are a group of clinical conditions characterized by genetic variant defects associated with a change in the amount or function of a protein in the coagulation system and a predisposition to thrombosis. Not all individuals with a genetic predisposition to thrombosis will develop VTE. The presence of inherited thrombophilia will presumably interact with other VTE risk factors to determine an individual’s VTE risk.

A number of conditions fall under the classification of inherited thrombophilias. Inherited thrombophilias include the following conditions, which are defined by defects in the coagulation cascade:

• Activated protein C resistance (factor V Leiden [FVL] variant)
• Prothrombin (factor II) gene variant (G20210A)
• Protein C deficiency
• Protein S deficiency
• Prothrombin deficiency
• Hyper-homocysteinemia (5,10-methylenetetrahydrofolate reductase [MTHFR] variant).

Genetic Testing

Genetic testing for gene variants associated with thrombophilias is available for FVL, the prothrombin G20210A variant, and MTHFR. Genetic testing for inherited thrombophilia can be considered in several clinical situations. Clinical situations addressed herein include the following:

• Assessment of thrombosis risk in asymptomatic patients (screening for inherited thrombophilia)
• Evaluation of a patient with established thrombosis, for consideration of a change in anticoagulant management based on results
• Evaluation of close relatives of patients with documented inherited thrombophilia or with a clinical and family history consistent with an inherited thrombophilia
• Evaluation of patients in other situations who are considered at high-risk for thrombosis (eg, pregnancy, planned major surgery, exogenous hormone use).

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Commercial thrombophilia genetic tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

The FDA has cleared several genetic tests for thrombophilia have been cleared for marketing by the FDA through the 510(k) process for use as an aid in the diagnosis of patients with suspected thrombophilia. Some of these tests are listed in Table 1.

Table 1. Genetic Tests for Thrombophilia Cleared by FDA

Test	Manufacturer	Cleared	510(k) No.
IMPACT Dx™ Factor V Leiden and Factor II Genotyping Test	Agena Biosciencea	06/14	K132978
Invader® Factor II, V, and MTHFR (677, 1298) tests	Hologic	04-06/11	K100943, K100980, K100987, K100496
VeraCode® Genotyping Test for Factor V and Factor II	Illumina	04/28/10	K093129
eSensor® Thrombophilia Risk Test, FII-FV, FII, FV and MTHFR (677, 1298) Genotyping Tests	GenMark Dxb	04/22/10	K093974
INFINITI™ System Assay for Factor II & Factor V	AutoGenomics	02/07/07	K060564
Xpert® Factor II and Factor V Genotyping Assay	Cepheid	09/18/09	K082118
Verigene® Factor F2, F5, and MTHFR Nucleic Acid Test	Nanosphere	10/11/07	K070597
Factor V Leiden Kit	Roche Diagnostics	12/17/03	K033607
Factor II (Prothrombin) G20210A Kit	Roche Diagnostics	12/20/03	K033612

FDA: Food and Drug Administration.
^a FDA marketing clearance was granted to Sequenom Bioscience before it was acquired by Agena Bioscience.
^b FDA marketing clearance was granted to Osmetech Molecular Diagnostics.

Other commercial laboratories may offer a variety of functional assays and genotyping tests for F2 (prothrombin, coagulation factor II) and F5 (coagulation factor V), and single or combined genotyping tests for MTHFR.

On April 6, 2017, the FDA permitted marketing of 23andMe Personal Genome Service Genetic Health Risk tests for 10 diseases or conditions. These direct-to-consumer tests are the first authorized by the FDA that provide information on an individual’s genetic predisposition to certain medical diseases or conditions, which may help to make decisions about lifestyle choices or to inform discussions with a health care professional. The 23andMe Genetic Health Risk tests work by isolating DNA from a saliva sample, which is then tested for more than 500000 genetic variants. The presence or absence of some of these variants is associated with an increased riskof developing any one of ten diseases or conditions. Testing for hereditary thrombophilia (two variants in the F5 and F2 genes; relevant for European descent) is included.

Related Policies

• Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disease (Policy #031 in the Pathology Section)

To access guidelines that apply for services provided August 1, 2017 and after to members enrolled in plans that HAVE elected to participate in the Program, please visit www.evicore.com/healthplan/Horizon_Lab.


I. Factor II/Prothrombin Testing

Genetic testing for Factor II/Prothrombin is considered medically necessary in individuals who meet ANY of the following lettered criteria:
A. Provoked venous thromboembolism (VTE) at a young age (<50 years); or
B. Recurrent VTE; or
C. Unusual VTE site, such as those involving the hepatic, portal, mesenteric, or cerebral veins; or
D. VTE associated with pregnancy or oral contraceptive use; or
E. VTE associated with hormone replacement therapy, selective estrogen receptor modulators (SERMs), or tamoxifen; or
F. Personal and close family history of VTE; or
G. Unprovoked VTE at any age; or
H. Family history of venous thrombosis at a young age (<50 years); or
I. Women experiencing recurrent pregnancy loss; or
J. Women with a history of other unexplained poor pregnancy outcomes, including severe preeclampsia, placental abruption, fetal growth retardation, and stillbirth; or
K. Family history of prothrombin gene mutation, particularly when results may impact oral contraceptive use or pregnancy management; or
L. Myocardial infarction before age 50, particularly in female smokers.

A. Genetic Testing for Factor V Leiden is considered medically necessary in individuals who meet ALL of the following lettered criteria:
1. Genetic Counseling
· Pre and post-test genetic counseling by an appropriate provider; AND

2. Previous Genetic Testing:
· No previous genetic testing for Factor V Leiden mutation; AND

3. Individual has at least one of the following risk factors suggesting a higher likelihood of having one or more factor V Leiden variants:
· Unprovoked/idiopathic venous thromboembolism at any age, or
· History of recurrent venous thromboembolism, or
· Venous thrombosis at an unusual site (e.g., cerebral, mesenteric, hepatic, and portal veins), or
· Venous thromboembolism during pregnancy or the puerperium, or
· Venous thromboembolism associated with the use of estrogen-containing therapies (e.g., oral contraceptives or hormone replacement therapy), or
· A personal history of any venous thromboembolism combined with a first-degree family member with venous thromboembolism before the age of 50 years, or
· Known factor V Leiden variant(s) identified in at least one 1st degree relative (parent, sibling, child). (Note: 2nd or 3rd degree relatives may be considered when 1st degree relatives are unavailable or unwilling to be tested); AND

4. Test results will be used for guiding management decisions beyond simply therapy of a current first venous thrombosis event or related future prophylaxis decisions.

B. The following factor V Leiden genotyping test applications are not considered medically necessary:
· Testing without clear evidence of an increased likelihood of having at least one factor V Leiden variant. This includes but is not limited to:
o Testing performed as part of expanded cardiovascular disease screening
o Testing based on the presence of conditions with unclear evidence including stroke, myocardial infarction, pregnancy loss, and pregnancy complications.

Genetic testing for variants in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene is considered investigational.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[INFORMATIONAL NOTE:
Supporting Guidelines and Evidence

Factor II

Consensus guidelines from the College of American Pathologists (CAP, 2002) related to diagnostic issues in thrombophilia have been issued. These guidelines were obtained by evaluating the literature since 1996 and were accepted if 70% consensus were reached. The guidelines are summarized below:

· Prothrombin G20210A testing should be performed in the following individuals:
o A first VTE before age 50 years
o A first unprovoked VTE at any age
o A history of recurrent VTE
o Venous thrombosis at unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
o VTE during pregnancy or the puerperium
o VTE associated with the use of oral contraceptives or hormone replacement therapy (HRT)
o A first VTE at any age in an individual with a first-degree family member with a VTE before age 50 years
o Women with unexplained fetal loss after the first trimester
· Prothrombin G20210A testing may be considered in the following individuals/circumstances, but is more controversial:
o Selected women with unexplained early-onset severe preeclampsia, placental abruption, or significant intrauterine growth retardation
o A first VTE related to tamoxifen or other selective estrogen receptor modulators (SERM)
o Female smokers under age 50 years with a myocardial infarction
o Individuals older than age 50 years with a first provoked VTE in the absence of malignancy or an intravascular device
o Asymptomatic adult family members of people with one or two known prothrombin G20210A alleles, especially those with a strong family history of VTE at a young age
o Asymptomatic female family members of people with known prothrombin thrombophilia who are pregnant or considering oral contraception or pregnancy
· Prothrombin G20210A testing is not recommended for the following:
o General population screening
o Routine initial testing during pregnancy
o Routine initial testing prior to the use of oral contraceptives, HRT, or SERMs
o Prenatal or newborn testing
o Routine testing in asymptomatic children
o Routine initial testing in adults with arterial thrombosis
· A consensus statement from the American College of Medical Genetics (ACMG, 2001) on factor V Leiden mutation analysis also provided guidance about prothrombin testing. These older guidelines generally agree with the CAP guidelines of 2002.

· An Agency for Health Care Research and Quality supported systematic review (AHRQ, 2009) found that, while mutation analysis is effective at identifying prothrombin mutations, "the incremental value of testing individuals with VTE for these mutations is uncertain. The literature does not conclusively show that testing individuals with VTE or their family members for FVL or prothrombin G20210A confers other harms or benefits. If testing is done in conjunction with education, it may increase knowledge about risk factors for VTE."

· Evaluation of Genomic Applications in Practice and Prevention Working Group (EGAPP, 2011) found sufficient evidence to recommend against Prothrombin mutation analysis in the following scenarios: 1. Adult with idiopathic VTE, 2. Asymptomatic adult family members of patient with VTE and a Prothrombin gene mutation for the purpose of considering primary prophylactic anticoagulation.

· Early consensus statements from the American College of Medical Genetics (ACMG, 2001)6 and the College of American Pathologists (CAP, 2002)7 recommended factor V Leiden (FVL) variant testing in the populations most likely to have a mutation. These included:
o VTE at a young age (<50 years)
o Recurrent VTE
o Unusual VTE site, such as those involving the hepatic, portal, mesenteric, or cerebral veins
o VTE associated with pregnancy or oral contraceptive use
o VTE associated with hormone replacement therapy, selective estrogen receptor modulators (SERMs), or tamoxifen
o Personal and close family history of VTE
o Unprovoked VTE at any age
o Family history of VTE at a young age (<50 years)

· An Agency for Health Care Research and Quality (AHRQ, 2009) supported systematic review found that, while variant analysis is effective at identifying FVL variants, "the incremental value of testing individuals with VTE for these mutations is uncertain. The literature does not conclusively show that testing individuals with VTE or their family members for FVL or prothrombin G20210A confers other harms or benefits. If testing is done in conjunction with education, it may increase knowledge about risk factors for VTE.”

· The Evaluation of Genomic Applications in Practice and Prevention (EGAPP, 2011), an initiative of the CDC Office of Public Health Genomics, evaluated the clinical utility evidence for two limited scenarios: 1) anticoagulation duration to prevent recurrence in people with idiopathic VTE and 2) primary VTE prevention in their at-risk relatives. They specifically exclude individuals with other risk factors for VTE, such as estrogen-containing therapy use. EGAPP makes the following recommendations:

o “[EGAPP] found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms.”
o Because anticoagulation is associated with significant risks and these mutations are associated with relatively low absolute VTE risk, the potential harms of overtreatment in these scenarios appears to outweigh the benefits of testing. However, test results may be used for other treatment decisions, such as anticoagulation in high-risk situations (e.g., surgery, pregnancy, long-distance travel), avoidance of estrogen-containing therapies, or the use of low-risk preventive measures (e.g., compression hose, activity counseling, smoking cessation). The authors noted that the evidence was insufficient to determine if testing might have utility in some situations, such as for influencing patient behavior or identifying those with homozygous mutations or combined thrombophilias. Therefore, these findings have limited application to the broader decision about who should be tested.
· Several other organizations have issued guidelines that help inform a decision about clinical utility by defining the change, or lack of change, in management of patients with known FVL thrombophilia in specific clinical circumstances.
o VTE management:
§ The American College of Chest Physicians (ACCP, 2008) recommends the same management for unprovoked VTE or VTE associated with a transient (reversible) risk factor (such as estrogen-containing therapies) irrespective of FVL results.9 These guidelines add “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 determinants of the risk of recurrence.”
§ Also note that the above referenced EGAPP (2011) study specifically addresses this test use and finds “There is no evidence that knowledge of FVL/PT mutation status in patients with VTE affects anticoagulation treatment to avoid recurrence.” “There is convincing evidence that anticoagulation beyond 3 months reduces recurrence of VTE, regardless of mutation status.”
o Pregnancy management:
§ The American College of Chest Physicians (ACCP, 2008) recommends the same management for VTE in a current pregnancy or for those with a prior VTE history during or outside of pregnancy irrespective of FVL results. However, if a higher risk thrombophilia is present, such as two Leiden variants or a combination of a Leiden and prothrombin variant, ACCP recommends some form of treatment and not simply surveillance.
§ Thrombophilia in pregnancy guidelines from the American College of Obstetricians and Gynecologists (ACOG, 2013) state:
· Testing is controversial and is “is useful only when results will affect management decisions, and is not useful in situations where treatment is indicated for other risk factors.” However, they add that screening “may be considered” for those with “A personal history of venous thromboembolism that was associated with a nonrecurrent risk factor (eg, fractures, surgery, and prolonged immobilization). The recurrence risk among untreated pregnant women with such a history and a thrombophilia was 16% (odds ratio, 6.5; 95% confidence interval, 0.8–56.3).”
· They add “Testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear if anticoagulation therapy reduces recurrence. Although there may be an association in these cases, there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or low molecular weight heparin (LMWH) prevents recurrence in these patients”
o Estrogen-containing therapy decisions:
§ American College of Obstetricians and Gynecologists (ACOG, 2006) contraceptive use guidelines state "Combination contraceptives are not recommended for women with a documented history of unexplained venous thromboembolism or venous thromboembolism associated with pregnancy or exogenous estrogen use, unless they are taking anticoagulants." Therefore, estrogen-containing drugs are contraindicated based on a history of VTE alone irrespective of FVL results.
§ American Association of Clinical Endocrinologists (AACE, 2011) menopause guidelines says only the following about menopausal hormone therapy (MHT): "Estrogen therapy has been associated with an increased risk of venous thromboembolic disease within 1 to 2 years after initiation of therapy. The increased relative risk (RR) is high, but the increased absolute risk is quite small…The incidence was greater with increasing age, obesity, and factor V Leiden mutations (45 [EL 1; RCT]). Women with a history of venous thromboembolic disease should be carefully advised about this risk when MHT is being considered.”
o Family history of a Leiden variant:
§ The above referenced EGAPP (2011) statement specifically addresses this test use for VTE prophylaxis and found “There is no evidence that knowledge of FVL/PT mutation status among asymptomatic family members of patients with VTE leads to anticoagulation aimed at avoiding initial episodes of VTE.”
§ American College of Obstetricians and Gynecologists (ACOG, 2010) states that testing is controversial and should only be done when the results will change management. However, they add that screening “may be considered” for those with “A first-degree relative (eg, parent or sibling) with a history of high-risk thrombophilia.”
§ Generally, estrogen-containing drugs must be approached with caution in anyone with a significant family history of VTE or known FVL and/or PT mutations, but no US evidence-based guidelines were identified that addressed testing in this scenario. Guidelines from the British Society for Haematology (BSH, 2010) most directly address FVL and PT testing in at-risk relatives for the purposes of deciding about estrogen-containing therapies. They recommend considering “alternative contraceptive or transdermal HRT [hormone replacement therapy]” when a first-degree relative: “has not been tested or is negative… Testing for heritable thrombophilia will provide an uncertain estimate of risk and is not recommended (1C).” or “has been tested and the result is positive… Offer alternative contraception, counsel that negative result would not exclude increased risk. However, testing may assist in counseling of selected women particularly if a high risk thrombophilia has been identified in the symptomatic relative (C).”
· The evidence supporting an association between FVL variants and thrombosis is adequate (clinical validity). However, there are no clinical situations in which FVL testing is either mandatory or specifically recommended in guidelines due to generally insufficient clinical utility data. Factor V Leiden genotyping may have some utility in limited circumstances where there is a recognized increased risk to have at least one mutation based on established risk factors, where the results will be used to direct management beyond the current VTE, and particularly when individuals are found to have a combination of more than one factor V Leiden mutation or additional genetic thrombophilias (despite the absence of reliable indicators). If testing is performed, there should be a specific plan for how the results will impact management.

· As part of the Choosing Wisely campaign, the American College of Medical Genetics and Genomics (2015) released “Five Things Physicians and Patients Should Question,” which states:
o “Don’t order MTHFR genetic testing for the risk assessment of hereditary thrombophilia. The common MTHFR gene variants, 677C>T and 1298A>G, are prevalent in the general population. Recent meta-analyses have disproven an association between the presence of these variants and venous thromboembolism.”
· Also as part of the Choosing Wisely campaign, the Society for Maternal Fetal Medicine (2014) released “Five Things Physicians and Patients Should Question,” which states:
o "Don’t do an inherited thrombophilia evaluation for women with histories of pregnancy loss, intrauterine growth restriction (IUGR), preeclampsia and abruption. Scientific data supporting a causal association between either methylenetetrahydrofolate reductase (MTHFR) polymorphisms or other common inherited thrombophilias and adverse pregnancy outcomes, such as recurrent pregnancy loss, severe preeclampsia and IUGR, are lacking."
· The American College of Medical Genetics and Genomics (ACMG, 2013) states:
o “It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia.”
· The American College of Obstetricians and Gynecologists (ACOG, 2013) states”
o “Because of the lack of association between either heterozygosity or homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and any negative pregnancy outcomes, including any increased risk for venous thromboembolism, screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended.”
· The National Society of Genetic Counselors (NSGC, 2005) state that MTHFR variant tesing is specifically not justified in the case of recurrent pregnancy loss based on available studies.]

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