RetiredCapital BluecrossPolicy MP 2.253

Genetic testing for inherited thrombophilia

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Policy governs medical necessity and coverage criteria for genetic and protein testing for inherited thrombophilias (e.g., Factor V Leiden, prothrombin variant, protein C/S, antithrombin) for Capital Bluecross members.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for inherited thrombophilia

Policy CodePolicy MP 2.253

Change TypeRetired policy (no material changes)

Effective DateJul 1, 2026

Last ReviewJul 21, 2025

Next Review DateN/A

Key ActionVerify member benefit and prior authorization requirements and document ICD-10 diagnosis codes that support medical necessity.

SourceLink

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RetiredCapital BluecrossPolicy MP 2.253

Genetic testing for inherited thrombophilia

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Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for inherited thrombophilia

Policy CodePolicy MP 2.253

Change TypeRetired policy (no material changes)

Effective DateJul 1, 2026

Last ReviewJul 21, 2025

Next Review DateN/A

Key ActionVerify member benefit and prior authorization requirements and document ICD-10 diagnosis codes that support medical necessity.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

~1/1000 yrVTE incidence

17–24%FVL prevalence in thrombosis

5–8%Prothrombin variant

≤0.2%Antithrombin defects

MTHFRLow-utility test

Coverage Criteria for Inherited Thrombophilia Testing

Genetic testing for Factor V Leiden and Factor II (prothrombin) — Covered indications

Covered when ANY one of the following indications is present:

Covered 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 a history of 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 <50 years who smoke tobacco 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 either a first‑degree relative with unprovoked VTE or VTE provoked by pregnancy/contraceptive use, or a first‑degree relative who is a known carrier for factor V Leiden and/or factor II c.*97G>A, or 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).

From policy section on Factor V Leiden and Factor II

Testing for protein C, protein S, and antithrombin III — Covered indications

Covered when ANY one of the following is present in individuals without recurrent VTE risk factors:

Covered 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; Individuals assigned female at birth <50 years who smoke tobacco and have a history of acute myocardial infarction; 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; Warfarin‑induced skin necrosis; Infants with 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.

From policy section on protein C, protein S, and antithrombin III

Situations considered for testing

Clinical situations in which genetic testing for inherited thrombophilia can be considered include:

Clinical situations: Assessment of thrombosis risk in asymptomatic patients (screening); Evaluation of a patient with established thrombosis to consider changes 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 inherited thrombophilia; Evaluation of patients in other high‑risk situations (e.g., pregnancy, planned major surgery, oral contraceptive use).

Listed clinical scenarios where testing may be considered per policy.

Evidence-based utility conclusions

Evidence summary regarding clinical utility:

Clinical utility conclusions: Genetic testing detects factor V Leiden and prothrombin variants that are associated with an increased risk of VTE, but the magnitude of association is modest (odds ratios commonly 1–2) and absolute risk remains low. Clinical utility of testing to guide initiation or duration of prophylactic anticoagulation has not been demonstrated; available evidence does not define a role for thrombophilia testing to direct prophylactic anticoagulation decisions. MTHFR polymorphism testing lacks established clinical validity and utility and should not be part of routine thrombophilia evaluation because it has minimal demonstrated clinical benefit.

Policy states insufficient evidence that testing improves health outcomes and notes potential harms from prophylactic anticoagulation decisions.

Covered Testing

Covered when medically necessary:

Covered testing codes: Testing represented by the enumerated procedure codes (e.g., 85307, 81241, 81400, CPT 85300–85307 series) is covered when medically necessary and when clinical criteria in the policy are met.

Exact medical necessity clinical criteria are detailed in the policy.

MTHFR (5,10-methylenetetrahydrofolate reductase) polymorphism testing and routine testing for arterial thrombotic disorders (e.g., coronary artery disease or ischemic stroke) are excluded from coverage. The policy states these services are considered investigational or not medically necessary because there is insufficient evidence to conclude they improve health outcomes or provide clinical benefit.

MTHFR polymorphism testing is specifically not recommended as part of the routine thrombophilia evaluation due to minimal clinical utility. Recent evidence and guideline statements indicate uncertain clinical validity and lack of demonstrated benefit from MTHFR genotyping for thrombosis risk assessment, and professional guidance advises against its use in routine workups.

The policy references the evidence base and guideline literature to clarify that routine thrombophilia testing and MTHFR polymorphism testing lack demonstrated clinical utility for many indications. Systematic reviews, randomized trials, and professional guidelines are cited to support the investigational or not medically necessary stance for routine MTHFR testing and for population screening approaches that do not affect management.

Routine genetic testing for individuals with a personal or family history of arterial thrombotic disorders is considered not medically necessary. The policy indicates insufficient evidence that routine thrombophilia testing in the setting of arterial disease (for example, coronary artery disease or ischemic stroke) improves clinical outcomes.

The evidence does not support use of thrombophilia testing to direct initiation or duration of prophylactic anticoagulation. The policy states that available data have not defined a role for thrombophilia testing to guide prophylactic anticoagulation decisions because the modest relative risks and low absolute event rates mean anticoagulation risks may outweigh potential benefits.

The American College of Medical Genetics (ACMG) practice guidance and other cited reviews conclude that MTHFR polymorphism testing lacks sufficient evidence of clinical validity and utility for routine use. The policy cites ACMG and related guidance as supporting the position that MTHFR genotyping is not clinically useful in standard thrombophilia evaluations.

Specific Covered Indications and Eligibility

Genotyping for Factor V Leiden and Factor II c.*97G>A when any covered indication in the policy is met (see criteria_sets).

Covered indication: Genotyping for Factor V Leiden and Factor II c.*97G>A when any covered indication in the policy is met; a positive or negative result must impact clinical management.

See policy criteria sets for specific indications.

Testing for protein C, protein S, and antithrombin III deficiencies when covered indications are met.

Covered indication: Testing for protein C, protein S, and antithrombin III deficiencies when the covered indications for these assays are met (see policy), including timing considerations (perform testing at least six weeks after acute event and while not on anticoagulants).

Clinical and timing requirements per policy.

Assessment of thrombosis risk in asymptomatic patients, evaluation of patients with established thrombosis for potential anticoagulant management changes, evaluation of close relatives of affected patients, and evaluation of patients in high-risk settings (pregnancy, planned major surgery, oral contraceptive use).

Procedure and Diagnosis Codes

Investigational; therefore, not coveredCPTNot Covered

81291

Covered when medically necessarymixedCovered

85307
81241
81400
85300
85301
85302
85303
85305
85306

Relevant ICD-10-CM diagnosis codesICD-10

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

Covered CPT/Procedure CodesCPTCovered

85307
81241
81400
85300
85301
85302
85303
85305
85306

Relevant ICD-10-CM Diagnosis CodesICD-10

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

Provider Actions, Authorization, and Documentation

Note

Benefit variation notice

This policy is subject to product-specific benefit variations; check the member's program for any differences (for example, FEP PPO follows the FEP Medical Policy Manual).

Prior Authorization

Prior authorization may be required for covered codes

Procedure codes listed as “Covered when medically necessary” may require prior authorization depending on the member’s benefit and medical necessity determination.

Covered procedure codes include 85307, 81241, 81400, 85300–85303, 85305–85306.

Prior Authorization

Verify PA for listed thrombophilia testing codes

Member Eligibility and Policy Applicability

Eligibility requirements for covered genetic and coagulation testing are determined by the specific clinical indications listed elsewhere in this policy. Coverage is limited to indications where test results would meaningfully impact clinical management, and coverage decisions depend on member benefit terms and documented medical necessity.

Providers must confirm member eligibility and benefit-specific prior authorization requirements prior to testing. Product-specific variations may alter coverage applicability.

Testing eligibility is generally tied to clinical scenarios described in the policy (for example, first unprovoked VTE <50 years, VTE at unusual sites, recurrent VTE, certain family-history patterns), and a documented indication that test results will affect management.

Timing considerations affect eligibility: testing should be performed at least six weeks after an acute thrombotic event and while the individual is not taking anticoagulants to ensure accurate interpretation.

Where applicable, formal genetic counseling is recommended when genetic testing for inherited thrombophilia is being considered; documentation of counseling and clinical rationale supports eligibility determinations.

Not Covered / Investigational Services

MTHFR polymorphism testing and routine testing for arterial thrombotic disorders are explicitly listed as not covered/investigational. Procedure code 81291 (MTHFR testing) is identified in the coding table as investigational and therefore not covered; the policy notes minimal clinical utility for MTHFR testing and excludes routine MTHFR genotyping from coverage.

Procedure code 81291 is listed as investigational and is not covered. The policy explains that MTHFR genetic testing has minimal clinical utility for thrombophilia evaluation and that tests billed under this code are subject to denial.

Routine MTHFR polymorphism testing is excluded from routine coverage because multiple guideline statements and meta-analyses have found no consistent association between common MTHFR variants, hyperhomocysteinemia, and thrombotic outcomes, yielding minimal clinical utility for genotyping in routine thrombophilia workups.

Background on Inherited Thrombophilia

Inherited thrombophilias are genetic conditions that increase risk of venous thrombosis. Commonly evaluated heritable defects include Factor V Leiden (F5) and the prothrombin G20210A / c.*97G>A (F2) variant; plasma assays assess protein C, protein S, and antithrombin III deficiencies. The policy notes that VTE incidence in the U.S. is approximately 1 per 1,000 person-years and that the presence of these genetic variants confers a modest increase in relative risk; testing is covered only for specific clinical indications where results will affect management.

Definitions

Inherited thrombophilia definition

DefinitionClinical conditions with genetic variant defects associated with predisposition to thrombosis (e.g., activated protein C resistance [Factor V Leiden], prothrombin G20210A, protein C deficiency, protein S deficiency, antithrombin deficiency).

Common examplesFactor V Leiden (accounts for up to ~50% of inherited thrombophilia syndromes); Prothrombin (F2) G20210A variant; Protein C, Protein S, and Antithrombin deficiencies.

Prevalence notesIn unselected patients with idiopathic thrombosis, Factor V Leiden positivity ~17–24%; Prothrombin G20210A ~5–8% in unselected thrombosis patients; antithrombin defects estimated ≤0.2%.

Clinical relevanceInherited thrombophilias predispose to venous thromboembolism and may be considered in specific clinical scenarios (see coverage criteria).

Protein C deficiency (definition)

Definition

Policy Revision History

2025-07-21Consensus reviewLatest

Consensus review with no change to policy statements and no coding changes.

2024-05-14Consensus Review

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

2023-07-26Ad Hoc Minor Review

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for inherited thrombophilia

Policy CodePolicy MP 2.253

Change TypeRetired policy (no material changes)

Effective DateJul 1, 2026

Last ReviewJul 21, 2025

Next Review DateN/A

Key ActionVerify member benefit and prior authorization requirements and document ICD-10 diagnosis codes that support medical necessity.

SourceLink

On This Page

Clinical scenarios: Assessment of thrombosis risk in asymptomatic patients (screening); Evaluation of patients with established thrombosis to consider potential changes in anticoagulant management; Evaluation of close relatives of affected patients with documented or suspected inherited thrombophilia; Evaluation of patients in high‑risk settings (pregnancy, planned major surgery, oral contraceptive use).

These scenarios are listed in the policy as situations where testing may be considered.

Testing for inherited thrombophilia when medically necessary and supported by the listed ICD-10 diagnoses.

Policy‑supported testing: Testing for inherited thrombophilia (Factor V Leiden, prothrombin G20210A / c.*97G>A, protein C, protein S, antithrombin deficiencies) is covered when medically necessary and supported by an appropriate ICD‑10 diagnosis documented in the medical record (for example D68.51, D68.52, D68.59, D68.61/D68.62, D68.69) and when clinical criteria in this policy are met.

Providers should document the diagnosis code(s) that support medical necessity and verify benefit‑specific prior authorization requirements.

Verify benefit-specific prior authorization requirements with Capital Bluecross before ordering or billing the thrombophilia testing codes enumerated in the policy.

Codes called out in the policy: 85300, 85301, 85302, 85303, 85305, 85306, 85307, 81241, 81400.

Step Therapy

Genetic counseling recommended

Formal genetic counseling is recommended in most cases when genetic testing for an inherited condition is being considered; counseling should be performed by someone experienced in genetic medicine and testing methods.

Counseling assists patients in understanding benefits, harms, and family implications of testing and may reduce inappropriate testing.

Note

Provider action

No additional provider action text available in this excerpt.

Note

Provider action

No additional provider action text available in this excerpt.

Documentation Required

Timing and clinical state for testing

Perform thrombophilia testing at least six weeks after an acute thrombotic event and only when the individual is not taking anticoagulants.

Documentation Required

Benefit and medical necessity documentation

Document medical necessity and verify member benefit terms; the code listing in the policy does not guarantee coverage and coverage determinations depend on member benefit information and documented medical necessity.

Documentation Required

Required diagnosis documentation

Document and retain ICD-10 diagnosis codes that support medical necessity (examples listed in the policy include D68.51, D68.52, D68.59, D68.61/D68.62, and D68.69).

Examples: D68.51 (Activated protein C resistance), D68.52 (Prothrombin gene mutation), D68.59 (Other primary thrombophilia), D68.61/D68.62 (Lupus anticoagulant / Antiphospholipid syndrome), D68.69 (Other thrombophilia).

Denial Risk

Routine arterial thrombosis testing denial risk

Routine testing for individuals with a personal or family history of arterial thrombotic disorders (e.g., coronary artery disease or ischemic stroke) is considered not medically necessary and is at risk for denial.

Denial Risk

Investigational code 81291 (denial risk)

Procedure code 81291 is designated investigational and therefore not covered; claims billed with 81291 for covered members are at risk for denial.

81291 is listed under “Investigational; therefore, not covered.”

Denial Risk

Coverage limited to listed procedure codes

Coverage is limited to the procedure codes enumerated as “Covered when medically necessary”; tests or procedure codes not listed in that section may be denied if medical necessity is not met and benefit does not cover them.

Documentation Required

Formal genetic counseling is recommended

Formal genetic counseling is recommended in most cases when genetic testing for an inherited condition is considered; counseling should be provided by an individual with expertise in genetic medicine/testing.

Counseling helps interpret results and assess potential impact on family members.

Note

Provider action

No additional provider action text available in this excerpt.

Note

Policy references professional guidance and evidence reviews

The policy references multiple professional guidelines and evidence reviews (ACMG, ACOG, NICE, Choosing Wisely, and others) to inform appropriate use of thrombophilia testing.

See referenced guidelines and evidence summaries cited in the policy for clinical context and recommended practices.

Documentation Required

Genetic testing should be accompanied by genetic counseling

Genetic testing should be accompanied by genetic counseling performed by an individual experienced in genetic medicine and genetic testing methods.

Note

Ordering clinician requirements not specified in excerpt

The excerpt does not specify which clinician types are authorized to order testing; refer to the broader policy or program-specific rules for ordering clinician requirements.

A genetic disorder caused by alterations in the PROC gene resulting in deficiency of protein C, a natural anticoagulant.

Clinical spectrumRanges from heterozygous (common) forms to rare severe congenital forms present at birth that can cause widespread small clots and life‑threatening complications in infancy.

Clinical consequencesIncreased risk of venous thrombosis and potential for severe neonatal complications in the homozygous/severe form.

Antithrombin deficiency (definition)

DefinitionA blood disorder characterized by reduced antithrombin, the primary inhibitor of thrombin, due to a genetic abnormality.

PathophysiologyAntithrombin limits coagulation by inhibiting thrombin; deficiency increases tendency to form venous thrombosis.

PrevalenceEstimated prevalence of antithrombin defects is low (maximum ~0.2%).

Protein S deficiency (definition)

DefinitionA rare inherited disorder caused by alterations in the PROS1 gene leading to deficiency of protein S, a cofactor in the protein C anticoagulant pathway.

Clinical presentationAssociated with recurrent venous thrombotic events, particularly deep vein thrombosis; severe cases in infants can cause purpura fulminans.

GeneticsCaused by pathogenic alterations in the PROS1 gene; severity varies with genetic status (heterozygous vs homozygous forms).

Inherited thrombophilia (alternate definition group)

ScopeInherited thrombophilia refers to genetic/hereditary coagulation disorders that predispose to thrombotic events, including FVL, prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin.

Representative conditionsActivated protein C resistance (Factor V Leiden), Prothrombin (F2) G20210A mutation, Protein C deficiency (PROC), Protein S deficiency (PROS1), Antithrombin deficiency.

Coding/diagnosis linkageRelevant ICD‑10 codes used to support medical necessity include D68.51 (activated protein C resistance), D68.52 (prothrombin gene mutation), D68.59/D68.61/D68.62/D68.69 (other thrombophilias).

Medically necessary indications expanded to state that a positive or negative genetic test result in women of reproductive age will impact clinical management; references updated.

2023-03-23Consensus Review

Consensus review with no change to policy statements; references updated and no coding changes.

2022-08-09Minor Review

Added medically necessary testing for protein C, protein S, and antithrombin III deficiencies and added CPT codes 85300–85303, 85305–85307; guidelines, background, references, and formatting updated.

2021-11-02Consensus Review

Consensus review with references updated and coding reviewed.

2021-08-27Administrative Update

Administrative update correcting spelling; note: administrative changes only.

2020-08-19Minor Review

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

2020-01-24Minor Review

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

2020-01-24Initial entry

Policy history records a minor review entry dated 01/24/2020 reflecting additions to medically necessary indications.