CurrentCapital BluecrossPolicy MP 2.253

Genetic Testing for Inherited Thrombophilia

This policy governs coverage and medical necessity criteria for genetic and related plasma testing for inherited thrombophilias (eg, Factor V Leiden, prothrombin G20210A, protein C/S, antithrombin III, MTHFR) for Capital BlueCross products to which the policy applies.

Policy Summary

PayerCapital Bluecross

PolicyGenetic Testing for Inherited Thrombophilia

Policy CodePolicy MP 2.253

Change TypeNo material changes

Effective DateJan 1, 2026

Next Review Date

Key ActionObtain formal genetic counseling and document testing performed at least six weeks after an acute thrombotic event when the patient is off anticoagulants.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

≈1/1,000VTE incidence

≈5%Lifetime VTE prevalence

17–24%FVL positivity (idiopathic)

5–8%Prothrombin G20210A positivity

≥6 weeksRecommended test timing

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

81291Investigational CPT

Coverage and Medical Necessity Criteria

inv-01: Factor V Leiden and Factor II (c.*97G>A) testing — medically necessary

Genetic testing for Factor V Leiden (FVL) and Factor II c.*97G>A may be considered medically necessary when ANY one of the following is met:

FVL/Factor II testing indications: A first unprovoked venous thromboembolism (VTE), especially <50 years; VTE at unusual sites (hepatic portal, mesenteric, cerebral veins); recurrent VTE; personal history of VTE with either two or more family members with VTE or one first-degree relative with VTE at a young age; individuals with low activated protein C (APC) resistance activity; individuals assigned female at birth under age 50 who smoke and have a history of acute myocardial infarction; siblings of individuals known to be homozygous for Factor V Leiden or Factor II c.*97G>A; individuals assigned female at birth of reproductive age with a first-degree relative with unprovoked VTE or VTE provoked by pregnancy or contraceptive use; individuals assigned female at birth of reproductive age with a first-degree relative who is a known carrier of FVL and/or Factor II c.*97G>A; personal history of VTE associated with a transient risk factor (pregnancy, estrogen-progestin contraceptive use, femoral fracture, surgery, or prolonged immobilization); and when a positive or negative genetic test result will impact clinical management (predictive, diagnostic, prognostic, or therapeutic).

inv-02: Protein C, S, Antithrombin testing — medically necessary

Testing for protein C, protein S, and antithrombin III deficiencies may be considered medically necessary when ANY one of the following is met:

Protein C / S / Antithrombin testing indications: A venous thromboembolism (VTE) before age 50; VTE at unusual sites (hepatic, mesenteric, cerebral veins); VTE with a strong family history of thrombotic disease; relatives of individuals with VTE before age 50.

inv-03: Additional medically necessary indications

Additional medically necessary indications: Individuals assigned female at birth who wish to start oral contraceptives with a personal or family history of VTE; VTE during pregnancy or individuals assigned female at birth taking oral contraceptives; individuals with warfarin-induced skin necrosis; infants who develop neonatal purpura fulminans; pediatric arterial ischemic stroke. Note: testing should be performed at least six weeks after an acute thrombotic event and while the individual is not taking anticoagulants.

inv-04: Not medically necessary / Investigational

Not recommended / investigational: Routine testing for individuals with a personal or family history of arterial thrombotic disorders (eg, coronary artery disease, ischemic stroke) is not medically necessary. MTHFR polymorphism testing is considered investigational and should not be ordered as part of routine thrombophilia evaluation due to minimal clinical utility.

inv-05: Permitted clinical scenarios (policy-listed)

Genetic testing for inherited thrombophilia may be considered in the following clinical situations:

Indications: Assessment of risk for thrombosis in asymptomatic patients (screening for inherited thrombophilia); evaluation of a patient with established thrombosis where results may influence anticoagulant management; evaluation of close relatives of patients with documented inherited thrombophilia or with a clinical and family history consistent with inherited thrombophilia; evaluation of patients in high-risk situations (eg, pregnancy, planned major surgery, or oral contraceptive use).

inv-06: Evidence summary and utility constraints

Evidence-based limitations and utility statements:

Utility limitations: Clinical validity demonstrated for Factor V Leiden and prothrombin variants with a modest increase in VTE risk (most odds ratios ~1–2); clinical utility for guiding initiation or duration of prophylactic anticoagulation has not been demonstrated and therefore testing has not been shown to improve health outcomes; MTHFR testing lacks demonstrated clinical validity and utility for thrombophilia evaluation and is discouraged.

Routine genetic testing for arterial thrombotic disorders (for example, coronary artery disease or ischemic stroke) is not medically necessary because there is insufficient evidence that such testing improves health outcomes. Additionally, MTHFR (5,10‑methylenetetrahydrofolate reductase) polymorphism testing is considered investigational given insufficient evidence to support clinical benefit when used in thrombophilia evaluation. [

Routine ordering of MTHFR polymorphism testing as part of a standard thrombophilia workup is discouraged because studies and guideline statements have demonstrated minimal clinical utility; professional societies recommend against MTHFR testing for evaluation of thrombosis or recurrent pregnancy loss. [

The American College of Medical Genetics (ACMG) practice guideline has concluded there is a lack of evidence supporting MTHFR polymorphism testing for thrombophilia evaluation. This guideline is cited in the policy as a basis for not recommending routine MTHFR testing due to uncertain clinical validity and utility. [

Per policy, MTHFR polymorphism testing is considered investigational and therefore not covered, and routine genetic testing for arterial thrombotic disorders is adjudicated as not medically necessary. These exclusions apply unless other policy-specified medically necessary indications are met. [

Available evidence does not support using thrombophilia genetic testing results to guide decisions about initiation or duration of prophylactic anticoagulation. The policy states that clinical utility for informing prophylactic anticoagulation timing or length has not been demonstrated and therefore testing for this purpose is not supported. [

ACMG and other referenced organizations have clarified that MTHFR polymorphism testing lacks evidence of benefit in thrombophilia evaluation; the policy therefore characterizes MTHFR testing as investigational and not routinely recommended. This aligns with the cited guideline literature and policy rationale. [

Specific Indications for Testing

inv-37: Testing for Factor V Leiden and Factor II c.*97G>A for the listed indications (first unprovoked VTE, unusual sites, recurrent VTE, family history patterns, low APC resistance, certain female reproductive risk scenarios, siblings of homozygotes, etc.).

Covered indications for FVL/F2 testing: Testing for Factor V Leiden and Factor II c.*97G>A is considered medically necessary for one or more of the policy-listed indications including: first unprovoked VTE (especially <50 years), VTE at unusual sites, recurrent VTE, specified family history patterns, low APC resistance, certain female reproductive–age risk scenarios, siblings of known homozygotes, and when results will impact clinical management.

inv-38: Testing for protein C, protein S, and antithrombin III deficiency for VTE before age 50, VTE at unusual sites, VTE with strong family history, or relatives of individuals with VTE before age 50.

Covered indications for protein C/S/AT testing: Testing for protein C, protein S, and antithrombin III deficiency is considered medically necessary for individuals with VTE before age 50; VTE at unusual sites; VTE with a strong family history of thrombotic disease; and relatives of individuals with VTE before age 50.

Who Qualifies for Testing

A personal history of venous thromboembolism (VTE) combined with a family history pattern supports testing in selected circumstances. Examples that qualify for targeted genetic testing include a personal VTE with two or more affected family members, or a personal VTE with a first‑degree relative who experienced VTE at a young age; such family-history criteria are specifically listed as indications for testing for Factor V Leiden and Prothrombin (Factor II). [

The policy lists family-history–based eligibility criteria for inherited thrombophilia testing: individuals with a personal VTE and multiple affected relatives, relatives of patients with VTE before age 50, or first‑degree relatives of known carriers are among scenarios where testing for Factor V Leiden, Prothrombin G20210A, or protein C/S/antithrombin deficiencies may be appropriate. These family-history patterns are explicit policy eligibility nodes. [

For evaluation of inherited thrombophilia, the policy prioritizes targeted testing when the individual’s personal and family history increases pretest probability—examples include VTE before age 50, VTE at unusual sites, recurrent events, or a close relative with early-onset VTE. These clinical-family history combinations are used to determine eligibility for genetic or plasma testing. [

The policy includes multiple eligibility nodes drawn from listed clinical scenarios: reproductive‑age individuals considering hormonal therapy with personal or family VTE history, VTE during pregnancy, neonatal purpura fulminans, warfarin‑induced skin necrosis, and pediatric arterial ischemic stroke—each noted as situations where testing may be medically necessary subject to the policy criteria. [

Testing for protein C, protein S, and antithrombin III deficiencies is considered medically necessary in specified circumstances such as VTE before age 50, VTE at unusual sites, strong family history of thrombotic disease, or relatives of individuals with early‑onset VTE; these policy-specified eligibility nodes guide when plasma and genetic testing are appropriate. [

Procedure and Diagnosis Codes

Investigational; therefore, not coveredCPTNot Covered

81291

Procedure code listed as investigational; not covered (document repeats 81291 multiple times)

Covered when medically necessarymixedCovered

81240	Listed under 'Covered when medically necessary'
81241	Listed under 'Covered when medically necessary'
81400	Listed under 'Covered when medically necessary'
85300	Listed under 'Covered when medically necessary'
85301	Listed under 'Covered when medically necessary'
85302	Listed under 'Covered when medically necessary'
85303	Listed under 'Covered when medically necessary'
85305	Listed under 'Covered when medically necessary'
85306	Listed under 'Covered when medically necessary'
85307	Listed under 'Covered when medically necessary'

Associated diagnosis codesICD-10

D68.51	Activated protein C resistance
D68.52	Prothrombin gene mutation
D68.59	Other primary thrombophilia
D68.62	Lupus anticoagulant syndrome
D68.61	Antiphospholipid syndrome
D68.69	Other thrombophilia

CPT codes added in 08/09/2022CPT

85300	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85301	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85302	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85303	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85305	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85306	Addition referenced in policy history (specific descriptor not provided in this excerpt)
85307	Addition referenced in policy history (specific descriptor not provided in this excerpt)

Actionable Guidance for Ordering and Billing

Prior Authorization

Product variation / Prior authorization note

This policy applies only to certain Capital Blue Cross programs and products and is subject to benefit variations. FEP PPO members should be referred to the FEP Medical Policy Manual for coverage details.

Products may have different prior authorization or benefit rules — verify member plan details before ordering genetic testing.
FEP PPO: https://www.fepblue.org/benefit-plans/medical-policies-and-utilization-management-guidelines/medical-policies

Prior Authorization

Check prior authorization for listed procedure codes

Check prior authorization requirements and member benefits before performing or billing for the procedures listed in the coding section. Coverage is determined by the member’s benefit plan and medical necessity.

Verify prior authorization for procedure codes listed in the policy’s coding information section.
Not all codes listed in the coding section are necessarily covered; final determination depends on member benefit information and medical necessity.

Services Not Covered

The policy explicitly lists MTHFR polymorphism testing as not covered because it is considered investigational and of minimal clinical utility in thrombophilia evaluation. Routine testing for arterial thrombotic disorders is similarly listed as not medically necessary. [

Use of CPT code 81291 is identified in the policy as investigational and not covered, and the policy reiterates that MTHFR testing is discouraged due to minimal clinical utility and lack of evidence supporting benefit when used in routine thrombophilia workups. [

The policy cites the ACMG practice guideline and other evidence reviews to support that MTHFR polymorphism testing lacks clinical validity and utility for thrombophilia evaluation; consequently, MTHFR testing is listed as not covered/investigational in the policy. [

Background and Rationale

Inherited thrombophilias are genetic predispositions to venous thrombosis. The most commonly encountered inherited variants discussed in the policy are Factor V Leiden (activated protein C resistance) and Prothrombin (Factor II) G20210A

Key Definitions

inv-30: Activated protein C resistance (FVL)

DefinitionActivated protein C resistance (Factor V Leiden [FVL] variant): a common inherited thrombophilia associated with increased venous thromboembolism (VTE) risk; FVL is the most common inherited thrombophilia, accounting for up to ~50% of inherited thrombophilia syndromes.

Prevalence in thrombosisIn unselected patients with idiopathic thrombosis, FVL positivity is ~17–24% versus 5–6% in controls.

Clinical relevanceIdentifying FVL may inform evaluation of recurrent or unusual-site VTE, family risk assessment, and certain reproductive risk scenarios (permitted clinical situations where testing may be considered).

Molecular noteFVL corresponds to a variant causing activated protein C resistance (commonly R506Q in F5).

inv-31: Prothrombin G20210A

Definition

Policy Revision History

2024-05-14Consensus Review

Consensus review completed; no change to policy statements, updated regulatory status and references; no coding changes.

2023-07-26Ad Hoc Minor Review

Medically necessary indications expanded to clarify that test results (positive or negative) in women of reproductive age will impact clinical management; references updated.

2023-03-23Consensus Review

Policy Summary

PayerCapital Bluecross

PolicyGenetic Testing for Inherited Thrombophilia

Policy CodePolicy MP 2.253

Change TypeNo material changes

Effective DateJan 1, 2026

Next Review Date

Key ActionObtain formal genetic counseling and document testing performed at least six weeks after an acute thrombotic event when the patient is off anticoagulants.

SourceLink

On This Page

inv-39: Testing for Factor V Leiden, prothrombin (F2) variants, and MTHFR in contexts including asymptomatic risk assessment, evaluation after thrombosis when management may change, family member evaluation, and high-risk situations (pregnancy, major surgery, OCP use).

Contexts for FVL/F2/MTHFR testing: Testing for Factor V Leiden, prothrombin (F2) variants, and MTHFR may be considered in contexts including risk assessment in asymptomatic patients, evaluation after thrombosis when results may influence anticoagulant management, evaluation of family members, and assessment in high-risk situations (pregnancy, planned major surgery, oral contraceptive use). Note: MTHFR testing is considered investigational and lacks demonstrated utility.

inv-40: Testing for Factor V Leiden, Prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin in clinically appropriate situations (policy history notes medically necessary indications added/expanded in prior reviews).

Policy history and clinical appropriateness: Testing for Factor V Leiden, Prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin is covered in clinically appropriate situations per the policy; policy history documents expansion of medically necessary indications in prior reviews (2020, 2022, 2023).

The policy specifies testing timing requirements to maximize diagnostic accuracy: testing should be performed at least six weeks after an acute thrombotic event and while the individual is not taking anticoagulants, to avoid false‑negative or confounded assay results. [

Additional policy eligibility nodes emphasize that testing should be limited to clinical situations where results are likely to affect management—such as evaluation after an unprovoked VTE, assessment of close relatives of affected individuals, and high‑risk situations (pregnancy, planned major surgery, or oral contraceptive use)—rather than routine population screening. [

Prior Authorization
Check prior authorization for thrombophilia testing codes
Prior authorization and benefit verification are recommended for thrombophilia-related testing. Confirm whether specific thrombophilia tests require prior authorization under the member’s plan.
Confirm prior authorization for tests for Factor V Leiden, prothrombin (Factor II) c.*97G>A, protein C, protein S, and antithrombin III where applicable.
Ensure testing timing recommendations are met (e.g., testing performed at least six weeks after an acute thrombotic event and while the individual is not on anticoagulants) when applicable to coverage determinations.

Denial Risk
Investigational code denial risk
Procedure code 81291 is listed as investigational and therefore not covered. Billing for investigational codes may lead to claim denial.
81291 — Investigational; therefore, not covered

Note
Policy history and coding reviews
The policy history documents coding reviews, additions, and confirms when no changes to policy statements or coding were made; providers should reference policy history when reconciling billing and coding.
Policy history entries (2020–2025) include coding reviews and additions (e.g., additions of CPT codes 85300–85307 in 08/09/2022).
Consensus reviews 03/23/2023, 05/14/2024, and 07/21/2025 noted no change to policy statements and no coding changes.

Documentation Required
Counseling and timing documentation
Genetic counseling is recommended in most cases when genetic testing for an inherited condition is considered. Document that counseling was provided and that testing timing recommendations were followed when relevant to medical necessity.
Formal genetic counseling by a clinician with expertise in genetic medicine is recommended prior to testing.
Document timing: testing should be performed at least six weeks after an acute thrombotic event and while the individual is not taking anticoagulants.
Include documentation that test results would impact clinical management when asserting medical necessity.

Documentation Required
Medical necessity and member benefit documentation
Coverage determinations depend on member benefits, medical necessity, and eligibility. Ensure documentation supports medical necessity per the policy criteria and verify member eligibility and benefit limits prior to testing.
Document how the requested testing meets one or more medically necessary indications specified in the policy (see policy criteria).
Verify member eligibility, benefit limitations, and prior authorization requirements before ordering tests to reduce denial risk.

Prothrombin (Factor II) G20210A: a gain-of-function mutation that increases prothrombin production, thrombin generation, and VTE risk.

Prevalence in thrombosisFound in approximately 5–8% of unselected patients with thrombosis (compared with ~2–2.5% of controls); overall prevalence about 2%.

Clinical relevanceTesting for G20210A may be considered in patients with first unprovoked VTE, unusual-site VTE, recurrent VTE, or relevant family history where results could affect management.

inv-32: Protein C / S / Antithrombin deficiencies

DefinitionProtein C, Protein S, and Antithrombin deficiencies: rare inherited deficiencies of natural anticoagulant proteins that predispose to venous thrombosis and, in severe forms, to neonatal complications.

Genetic basisProtein C deficiency is caused by mutations in PROC; Protein S deficiency by PROS1 alterations; Antithrombin deficiency by SERPINC1 variants (genetic defects described in policy).

Clinical relevanceTesting indicated for VTE before age 50, VTE at unusual sites, strong family history of thrombotic disease, or relatives of individuals with early-onset VTE.

inv-33: Protein C deficiency

DefinitionProtein C deficiency: a genetic disorder from PROC mutations leading to reduced protein C, a natural anticoagulant; heterozygous forms are more common, homozygous/severe forms can present in infancy with life-threatening thrombosis.

Clinical manifestationsAssociated with increased risk of deep vein thrombosis and, in severe congenital forms, neonatal purpura fulminans.

Testing indicationsConsider testing for protein C deficiency in patients with VTE before age 50, VTE at unusual sites, recurrent VTE, or a strong family history where results would inform management.

inv-34: Antithrombin deficiency

DefinitionAntithrombin deficiency: congenital reduction in antithrombin (primary inhibitor of thrombin) leading to a predisposition to venous thrombosis; prevalence estimated up to ~0.2%.

Clinical significanceAntithrombin limits clot formation; deficiency increases thrombotic tendency and may warrant testing in early-onset or familial VTE.

Testing contextConsider testing in VTE before age 50, unusual-site VTE, recurrent events, or relatives of affected individuals to guide risk assessment and management.

inv-35: Protein S deficiency

DefinitionProtein S deficiency: rare inherited disorder due to PROS1 gene alterations, associated with recurrent venous thromboembolism and increased DVT risk; severe cases can cause neonatal purpura fulminans.

Clinical impactAffected individuals are at elevated risk for recurrent clots and emboli; testing is considered in early-onset, unusual-site, or familial VTE.

Relation to other defectsOften considered alongside protein C and antithrombin testing as part of evaluation for inherited thrombophilia when clinically indicated.

inv-36: Inherited thrombophilia

DefinitionInherited thrombophilia: genetic predisposition to thrombosis due to variants such as Factor V Leiden (F5 R506Q), Prothrombin G20210A, or deficiencies of protein C, protein S, or antithrombin.

Clinical scopeIncludes common single-gene variants (FVL, prothrombin G20210A) and rarer coagulation inhibitor deficiencies; testing may be considered in specific clinical scenarios (first unprovoked VTE, unusual sites, strong family history, reproductive risk contexts).

Evidence basePolicy references multiple reviews and cohort studies supporting modest associations for common variants and outlines limitations in clinical utility for guiding prophylactic anticoagulation decisions.

Consensus review completed; no change to policy statements, references updated; no coding changes.

2022-08-09Minor Review

Added medically necessary testing for protein C, protein S, and antithrombin III deficiencies and added CPT codes 85300, 85301, 85302, 85303, 85305, 85306, 85307.

2021-11-02Consensus Review

Consensus review completed; references updated and coding reviewed.

2021-08-27Administrative Update

Administrative update correcting spelling in policy text.

2020-08-19Minor Review

Medically necessary indications for Factor II and Factor V expanded; investigational statement for routine testing and MTHFR clarified; guidelines, background, references, and coding reviewed.

2020-01-24Minor Review

Added medically necessary indications per American College of Medical Genetics; references and coding reviewed.

2025-07-21Consensus ReviewLatest

Consensus review completed; no change to policy statements and no coding changes.