Description of Procedure or Service

Definitions

Venous thrombosis refers to a clot present in a blood vessel. The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism (PE) (Bauer & Lip, 2018). Thrombophilia refer to hereditary and/or acquired abnormalities of hemostasis that predispose patients to thrombosis (Stevens et al., 2016).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for venous thrombosis risk testing when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Venous Thrombosis Risk Testing is covered

1. Genetic testing for Factor V Leiden mutation and Prothrombin gene G20210A mutation is considered medically necessary in patients without recurrent VTE risk factors (for example, surgery, prolonged immobilization, collagen vascular disease, malignancy, certain hematologic disorders) in any of the following situations:
   1. Age <50, any venous thrombosis
   2. Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins)
   3. Recurrent venous thrombosis
   4. Venous thrombosis and a strong family history of thrombotic disease
   5. Venous thrombosis in pregnant women or in women taking oral contraceptives
   6. First and second degree relatives of individuals with venous thrombosis under age 50
   7. Myocardial infarction in female smokers under age 50
   8. Before administration of oral contraceptives, targeted testing of women with a personal or family history of venous thrombosis
2. Testing for protein C deficiency, protein S deficiency and antithrombin III deficiency is considered medically necessary in patients without recurrent VTE risk factors (for example, surgery, prolonged immobilization, collagen vascular disease, malignancy, certain hematologic disorders) in any of the following situations. Testing should be performed at least six weeks after acute thrombotic event and while the patient is not taking anticoagulants
   1. Age <50, any venous thrombosis
   2. Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins)
   3. Recurrent venous thrombosis
   4. Venous thrombosis and a strong family history of thrombotic disease
   5. Venous thrombosis in pregnant women or in women taking oral contraceptives
   6. Relatives of individuals with venous thrombosis under age 50
   7. Myocardial infarction in female smokers under age 50
   8. Before administration of oral contraceptives, targeted testing of women with a personal or family history of venous thrombosis
   9. Individuals with warfarin induced skin necrosis
   10. Infants who develop Neonatal Purpura Fulminans

When Venous Thrombosis Risk Testing is not covered

1. Genetic Testing for inherited thrombophilia is considered investigational for the following situations:
   1. Evaluation of recurrent fetal loss, placental abruption, preeclampsia, or fetal growth restriction
   2. Evaluation of arterial thrombosis not attributable to paradoxical emboli
   3. Routine screening in the general population
   4. Routine screening of asymptomatic women considering oral contraceptive use or hormone replacement therapy
   5. Routine screening of asymptomatic pregnant women
   6. Prenatal or preimplantation testing
   7. Routine newborn screening
2. Testing for other factors, including the factor V HR2 variant, or prothrombin G1199A variant, or factor VII R353Q variant, or factor 13B V34L variant or PAI-1, as well as multi-gene panel testing is considered investigational.
3. MTHFR genetic testing is not considered medically necessary for hypercoagulable evaluation or for “at risk” family members.

Policy Guidelines

Background

Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, or both, affects an estimated 300 000 to 600 000 individuals in the United States annually resulting in significant morbidity and mortality (Gupta, Sarode, & Nagalla, 2017). The etiology of thrombosis is multifactorial, thus determination of risk is challenging.

Hypercoagulability can be acquired or hereditary. Inherited risk factors include genetic mutation of the coagulation system. Known loss of function mutations include those affecting antithrombin (AT), protein C (PC) and protein S (PS) Gain of function mutations include the factor V Leiden (FVL) and the prothrombin gene 20210 A/G (PGM) mutations (Stevens et al., 2016). VTE has a strong genetic basis, with approximately 50–60% of the variance in VTE incidence attributed to genetic effects(Crous-Bou, Harrington, & Kabrhel, 2016). Although patients with inherited thrombophilia have an increased relative risk of a first VTE, assessing the risk of recurrent VTE is the same in patients with and those without inherited thrombophilia (Connors, 2017). Acquired risk factors or predisposing conditions for thrombosis include a prior thrombotic event, recent major surgery, presence of a central venous catheter, trauma, immobilization, malignancy, pregnancy, the use of oral contraceptives or heparin, myeloproliferative disorders, antiphospholipid syndrome (APS), and a number of other major medical illnesses(Bauer & Lip, 2018). Patients with acquired hypercoagulability have an increased risk of venous thrombosis, arterial thrombosis, or both, however, have a low risk of recurrence, regardless of thrombophilia status(Connors, 2017).

Kudo et al (2016) evaluated the utility of thrombophilia testing and concluded “The practice of thrombophilia testing in public hospitals was frequently inconsistent with guidelines, and did not significantly influence clinical decisions. There was higher yield of testing in patients with recurrent episodes of VTE and possibly in patients with unprovoked VTE.”

Recent review by Connnors (2017) states that “Although thrombophilia status is often used in making decisions about secondary prophylaxis after a first provoked VTE or about primary prophylaxis in positive family members at times of added or increased risk, data supporting this practice are limited. There are no data suggesting that patients with VTE and inherited thrombophilia should be treated differently from those who have VTE without thrombophilia; both groups should benefit from the use of VTE prophylaxis at times of increased major risk. A randomized, controlled trial addressing the question of whether testing for inherited thrombophilia at the time of a first VTE alters the risk of recurrence was stopped early because of low enrollment and lack of funding”.

Gupta et al (2017) concur stating that “Inherited thrombophilias may be more common in selected patients with unprovoked VTE, including those younger than 45 years, or those with a family history of VTE at young age. Even in these selected populations, inherited thrombophilia testing should not routinely change management of anticoagulation, although it may allow genetic counseling and testing of first-degree relatives.”

Applicable Federal Regulations

N/A

Guidelines and Recommendations

The American College of Medical Genetics and Genomics (ACMG) (Grody, Griffin, Taylor, Korf, & Heit, 2001; Spector et al., 2005)

Guidelines indicate that testing should be performed in at least the following circumstances (these are the same general recommendations for testing for any thrombophilia):

• Age <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.

Testing may also be considered in the following situations:

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

Random screening of the general population for factor V Leiden is not recommended.

Routine testing is not recommended for patients with a personal or family history of arterial thrombotic disorders (e.g., acute coronary syndromes or stroke) except for the special situation of myocardial infarction in young female smokers. Testing may be worthwhile for young patients (<50 years of age) who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease.

Neither prenatal testing nor routine newborn screening is recommended.

In contrast to the factor V Leiden recommendations, the ACMG does not support testing for MTHFR mutations “as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss” or for “at-risk family members.”

The American College of Obstetricians and Gynecologists (ACOG, 2013)

Clinical management guidelines recommend that screening for inherited thrombophilia “may be considered in the following clinical settings:

1. “A personal history of venous thromboembolism that was associated with a non-recurrent risk factor
2. “A first degree relative (parent or sibling) with a history of high-risk thrombophilia.”

ACOG does not recommend “testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption … because it is unclear if anticoagulation reduces recurrence.” Additionally, ACOG does not support testing for inherited thrombophilia in women with a history of preeclampsia or fetal growth restriction.

ACOG recommends that screening for inherited thrombophilias should include testing for “factor V Leiden mutation; prothrombin G20210A mutation; and antithrombin, protein C, and protein S deficiencies.” Also, it is recommended that testing be performed “(after 6 weeks) from the thrombotic event and while the patient is not pregnant and not taking anticoagulation or hormonal therapy.” 

ACOG (Hickey, Curry, & Toriello, 2013) does not support testing for MTHFR variants, due to the lack of correlation with negative pregnancy outcomes.

EGAPP (Evaluation of Genomic Applications in Practice and Prevention) (EGAPP, 2011)

Recommendation

“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group 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. The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE."

American Society of Hematology (ASH, 2013)

Recommend that: “Thrombophilia testing is costly and can result in harm to patients if the duration of anticoagulation is inappropriately prolonged or if patients are incorrectly labeled as thrombophilic. Thrombophilia testing does not change the management of VTEs occurring in the setting of major transient VTE risk factors. When VTE occurs in the setting of pregnancy or hormonal therapy, or when there is a strong family history plus a major transient risk factor, the role of thrombophilia testing is complex and patients and clinicians are advised to seek guidance from an expert in VTE.”

The Anticoagulation Forum published guidance in the Journal of Thrombosis and Thrombolysis on (Stevens et al., 2016):

1. Do not perform thrombophilia testing following an episode of provoked VTE. A positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE.
2. Do not perform thrombophilia testing in patients following an episode of unprovoked VTE. If a patient with unprovoked VTE and low bleeding risk is planning to stop anticoagulation, test for thrombophilia if test results would change this decision. A negative thrombophilia evaluation is not a sufficient basis to stop anticoagulants following an episode of unprovoked VTE in a patient with low bleeding risk and willingness to continue therapy. Heterozygosity for FVL or PGM does not increase the predicted risk of recurrence after unprovoked VTE to a clinically significant degree.
3. Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia. As a family history of VTE confers an excess risk of thrombosis, relatives should be counseled regarding use of prophylaxis in high risk situations.
4. Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia who are contemplating use of estrogen. If a woman contemplating estrogen use has a first-degree relative with VTE and a known hereditary thrombophilia, test for that thrombophilia if the result would change the decision to use estrogen.
5. Do not perform thrombophilia testing at the time of VTE diagnosis or during the initial 3-month course of anticoagulant therapy. When testing for thrombophilia following VTE, use either a 2-stage testing approach (see text) or perform testing after a minimum of 3 months of anticoagulant therapy has been completed, and anticoagulants have been held.

Pregnancy, sex and estrogen use reduce the levels of Protein S. Use of sex specific reference intervals, and testing prior to pregnancy or while not receiving estrogen preparations is preferred.

Recent guidance published in the New England Journal of medicine by Gupta was summarized by Barnes for the American College of Cardiology:

1. “Venous thromboembolism (VTE) affects an estimated 300,000-600,000 patients annually in the United States.
2. The risk of VTE recurrence is best predicted by whether the initial VTE episode was provoked or unprovoked, not the results of inherited thrombophilia testing.
3. Most patients with a provoked VTE have recently undergone surgery, immobility, trauma, or have a concurrent cancer diagnosis. Concurrent use of hormones (e.g., estrogencontaining contraceptive pills) is also frequently considered a provoking factor for VTE development.
4. For patients with a first provoked VTE event, guidelines recommend anticoagulation for only 3 months (not longer). Prolonged anticoagulation is associated with an increased risk of bleeding that outweighs the risk of VTE recurrence for these patients.
5. Patients with an unprovoked VTE (none of the provoking risk factors listed above) require longer anticoagulation due to a higher risk of recurrence that outweighs the risk of bleeding associated with long-term anticoagulation therapy.
6. Thrombophilia testing performed in the setting of an acute clot or ongoing anticoagulation therapy will often result in spurious results (usually false positive). For example, natural anticoagulants (e.g., protein C and S, antithrombin) are consumed during an acute thrombotic event and the levels can be reduced by ongoing anticoagulant therapy.
7. A recent study identified that up to 55% of Medicare patients with provoked VTE had undergone inappropriate thrombophilia testing, associated with significant cost to the healthcare system.
8. While thrombophilia testing rarely impacts management decisions about anticoagulation therapy, it may be beneficial for genetic testing purposes in patients presenting with a first unprovoked VTE at a young age (e.g., <45 years) or at an unusual site.
9. For patients with unprovoked VTE at a young age, VTE at an unusual site, arterial thrombosis, or pregnancy morbidity, testing for antiphospholipid antibodies, JAK2 mutation, and paroxysmal nocturnal hemoglobinuria may be beneficial.
10. There is no role for extensive cancer screening (e.g., computed tomography scanning) in patients with VTE. Only routine, age-appropriate cancer screening is recommended.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81240, 81241, 81291, 81400, 81479, 85300, 85301, 85302, 85303, 85305, 85306, 85307,

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

ACOG. (2013). ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol, 122(3), 706-717. doi:10.1097/01.AOG.0000433981.36184.4e

ASH. (2013). ASH - Testing for thromboembolism | Choosing Wisely.
http://www.choosingwisely.org/clinician-lists/american-society-hematology-testing-forthrombophilia-in-adults/

Bauer, K., & Lip, G. (2018). Overview of the causes of venous thrombosis - UpToDate. In G. Finlay (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of-thecauses-of-venousthrombosis?search=thrombophilia&usage_type=default&source=search_result&selectedTitle=1~1 50&display_rank=1.

Connors, J. M. (2017). Thrombophilia Testing and Venous Thrombosis. In N Engl J Med (Vol. 377, pp. 2298). United States.

Crous-Bou, M., Harrington, L. B., & Kabrhel, C. (2016). Environmental and genetic risk factors associated with venous thromboembolism. Semin Thromb Hemost, 42(8), 808-820. doi:10.1055/s0036-1592333

EGAPP. (2011). Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med, 13(1), 67-76. doi:10.1097/GIM.0b013e3181fbe46f

Grody, W. W., Griffin, J. H., Taylor, A. K., Korf, B. R., & Heit, J. A. (2001). American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med, 3(2), 139- 148. doi:10.109700125817-200103000-00009

Gupta, A., Sarode, R., & Nagalla, S. (2017). Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Intern Med, 177(8), 1195-1196. doi:10.1001/jamainternmed.2017.1815

Hickey, S. E., Curry, C. J., & Toriello, H. V. (2013). ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med, 15(2), 153-156. doi:10.1038/gim.2012.165

Kudo, M., Lee, H. L., Yang, I. A., & Masel, P. J. (2016). Utility of thrombophilia testing in patients with venous thrombo-embolism. J Thorac Dis, 8(12), 3697-3703. doi:10.21037/jtd.2016.12.40

Spector, E. B., Grody, W. W., Matteson, C. J., Palomaki, G. E., Bellissimo, D. B., Wolff, D. J., . . . Richards, C. S. (2005). Technical standards and guidelines: venous thromboembolism (Factor V Leiden and prothrombin 20210G >A testing): a disease-specific supplement to the standards and guidelines for clinical genetics laboratories. Genet Med, 7(6), 444-453. doi:10.109701.gim.0000172641.57755.3a

Stevens, S. M., Woller, S. C., Bauer, K. A., Kasthuri, R., Cushman, M., Streiff, M., . . . Douketis, J. D. (2016). Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis, 41, 154-164. doi:10.1007/s11239-015-1316-1

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for venous thrombosis risk testing when it is determined to be medically necessary because the criteria and guidelines have been met. Medical Director review 1/1/2019. (jd)