Blue Cross Blue Shield - Tennessee thrombosis testing Coverage | OpenPayer

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Blue Cross Blue Shield - Tennessee thrombosis testing Coverage | OpenPayer

Coverage criteria and evidence-based recommendations

Plasma inhibitor testing - Covered Indications

Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency MEETS COVERAGE CRITERIA when ANY of the following clinical scenarios apply:

Covered indications for plasma testing: a) Individuals <50 years with any deep venous thrombosis (DVT).

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

b) Individuals who have experienced a DVT in unusual sites (e.g., hepatic, mesenteric, or cerebral veins).

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

c) Individuals who have experienced a DVT and who have a strong family history of thrombotic disease.

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

d) Individuals who are pregnant or taking oral contraceptives and who have experienced a DVT.

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

e) First- and second-degree relatives of individuals who experienced a DVT before age 50 (see Note 2 for relative definitions).

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

f) Women under age 50 who smoke and have suffered a myocardial infarction.

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

g) Targeted testing prior to administration of estrogen-containing oral contraceptives or other estrogen therapy when personal or family history of DVT suggests testing would change management.

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

h) Pediatric individuals who have suffered pediatric arterial ischemic stroke where evaluation for thrombophilia is indicated.

Perform assays >=6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform inhibitor amount/function assays prior to any molecular testing.

Coverage criteria and limitations (operational notes)

Plasma testing for protein C, protein S, and antithrombin III deficiency MEETS COVERAGE in the clinical scenarios below; perform inhibitor amount/function assays before any molecular testing and observe timing requirements.

Ordering and timing requirements: Assays for clotting inhibitor amount and function should be performed prior to any molecular (genetic) testing.>= 6 weeks after acute thrombotic event and while off anticoagulants

Document timing relative to anticoagulant therapy; testing during acute clot or while on anticoagulation may yield spurious results.

Documentation: When testing is performed after VTE, document timing relative to anticoagulant therapy and completion of initial therapy; indicate the clinical rationale (age, site, recurrence, family history) that justifies testing.

ACMG technical standard and Anticoagulation Forum recommend documentation to support testing decisions.

Deferral/limitations: Do not perform thrombophilia testing at the time of VTE diagnosis or during the initial 3-month course of anticoagulant therapy; defer testing until after completion of initial therapy or per specific agent-based intervals (e.g., 2 weeks after warfarin, 2 days after DOACs).

Guideline-based coverage considerations

Recommendations and testing stance from cited professional societies

D-dimer use in suspected PE/DVT: Use D-dimer measurement with a highly sensitive assay in outpatients or emergency department patients with low or intermediate (or 'unlikely') clinical probability to reduce imaging; consider age-adjusted or clinical-probability–adapted cut-offs; do not use D-dimer to exclude PE when clinical probability is high.

ESC 2019 and ESC DVT update 2021 recommend highly sensitive assays and adaptive cut-offs.

Assay types recommended: ELISA D-dimer or highly sensitive immunoturbidimetric tests are suggested to exclude DVT in 'unlikely' clinical probability patients.

ESC Working Group 2021 and reimbursement policy references support assay preferences.

Thrombophilia screening stance: Routine laboratory screening for heritable thrombophilias is not recommended; homocysteine assay should not be included in thrombophilia workups.

SIGN (2014) and ASCLS Choosing Wisely (2021) advise against routine screening and homocysteine testing.

Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities) is explicitly stated as not meeting coverage criteria and is excluded from coverage. The policy notes limited evidence that such testing changes acute management, particularly in pediatric populations, and highlights that routine testing in these contexts lacks demonstrated clinical utility.

More broadly, testing to assess DVT risk as part of pre-transplant evaluations is also described as not meeting coverage criteria because available studies do not support benefit or cost-effectiveness for altering management in that setting.

The policy states that the activated protein C (aPC) resistance assay DOES NOT MEET COVERAGE CRITERIA. Rationale includes interpretive difficulties, interference from other conditions (for example, lupus anticoagulant) or anticoagulant therapy, and the need for confirmatory genetic testing (e.g., Factor V Leiden genotyping) when a functional assay is positive.

Because of these limitations and the decreasing cost and greater clarity of direct genetic testing, the document indicates that aPC resistance assays are infrequently performed and are not supported as a covered standalone diagnostic test.

Professional guidance from ACMG and ACOG is cited to discourage use of MTHFR variant testing and routine fasting homocysteine measurement for thrombophilia assessment or pregnancy-related screening. ACMG states MTHFR testing lacks correlation with adverse pregnancy outcomes, and ACOG recommends against MTHFR or fasting homocysteine screening because they do not reliably inform management.

ACOG’s updated practice guidance specifies recommended inherited thrombophilia tests (Factor V Leiden, prothrombin G20210A, and antithrombin/protein C/protein S deficiencies) while advising against MTHFR and fasting homocysteine as part of routine screening for pregnancy-related risk assessment.

Guideline statements from SIGN and ASCLS are cited to emphasize that routine laboratory screening for heritable thrombophilias is not recommended. The policy further notes that a homocysteine assay should not be included as part of thrombophilia testing panels because elevated homocysteine is not a clotting disorder and does not belong in routine thrombophilia workups.

The policy underscores that testing should be targeted to clinical scenarios where results will affect management (for example, young age at first VTE, unusual site, strong family history), rather than used for broad population screening.

The Society for Vascular Medicine / Choosing Wisely recommendation is referenced: do not perform routine hypercoagulable testing for patients who develop a first episode of DVT when there is a known provoking cause. The policy adopts this stance, indicating such testing is unnecessary and unlikely to change immediate management.

This guidance is presented to help clinicians avoid low-yield testing after a provoked DVT and to reduce unnecessary costs and potential misinterpretation of results obtained during or soon after an acute event.

Summary: the policy lists several specific tests or indications that are not covered including the routine use of the aPC resistance assay, testing for superficial venous thrombosis, and performing DVT risk testing as part of pre-transplant evaluations. These items are identified as lacking sufficient evidence to be beneficial or to alter patient management.

Requests for these tests may therefore be subject to denial under the coverage policy unless compelling, guideline-supported justification is provided that aligns with covered indications elsewhere in the document.

The policy states that routine thrombophilia testing is not supported for the majority of patients with VTE, including many with provoked events, because testing seldom influences decisions about anticoagulation duration or acute management. The ACC guidance summarized in the document emphasizes that recurrence risk is driven primarily by whether the VTE was provoked or unprovoked, not by inherited thrombophilia test results.

Testing may be considered in selected situations — for example, a first unprovoked VTE at a young age or thrombosis at an unusual site — but routine panels for most patients are discouraged as they rarely change clinical care.

The policy discourages ordering hypercoagulable testing after a provoked first DVT; results rarely affect the recommended 3-month anticoagulation course for provoked events and may produce spurious findings if performed during the acute event or while on anticoagulation.

Clinicians are advised to defer testing until it would influence management decisions and to document the clinical rationale (for example, age, site of thrombosis, recurrence, or relevant family history) when testing is pursued.

Indications where testing is covered

Plasma testing for protein C, protein S, and antithrombin III deficiency — ordering and timing

Plasma testing for protein C, protein S, and antithrombin III deficiency should be performed in the following clinical scenarios; perform inhibitor amount/function assays before molecular testing and observe timing guidance.

Pre-molecular testing requirement: Perform plasma inhibitor amount and function assays prior to any molecular or genetic testing for thrombophilia.

This prevents unnecessary genetic testing if plasma assays do not indicate deficiency.

Clinical scenarios warranting plasma inhibitor testing: First unprovoked VTE at a young age (<50), VTE at unusual sites (hepatic, mesenteric, cerebral), recurrent VTE, strong family history of thrombotic disease, or when test results would change clinical management decisions (e.g., contraception or pregnancy planning).

Testing should be timed >=6 weeks after acute event and while off anticoagulants.

Excluded or discouraged scenarios:

Tests and uses considered not medically necessary

The policy explicitly lists as NOT COVERED: activated protein C (aPC) resistance assays, testing to assess DVT risk as part of pre-transplant evaluations, and targeted testing for superficial venous thrombosis. These exclusions reflect limited evidence of clinical benefit and potential for misleading or uninterpretable results.

Providers requesting these tests should be aware that coverage is not supported except in rare, guideline-justified circumstances documented in the policy.

The policy denotes MTHFR variant testing and routine fasting homocysteine measurement for thrombophilia assessment or pregnancy screening as not covered. ACMG and ACOG guidance cited in the document state these tests lack association with adverse pregnancy outcomes and do not inform management decisions.

As such, these assays should not be ordered for routine thrombophilia or prenatal screening purposes under the coverage policy.

Hypercoagulable workups performed while the patient is receiving direct factor Xa or direct thrombin inhibitors are discouraged and listed as not covered because anticoagulant therapy can render many thrombophilia assays uninterpretable or misleading.

The document cites Choosing Wisely guidance that testing in the setting of DOACs or direct thrombin inhibitors may produce inaccurate results and therefore should be avoided until testing can be performed off anticoagulation.

Routine screening for heritable thrombophilias is identified as not covered in accordance with guideline statements (SIGN 2014) advising against general population screening. The policy also states that ordering a homocysteine assay as part of thrombophilia panels is not recommended (ASCLS Choosing Wisely 2021) and therefore is considered not covered.

Procedure and billing codes

Thrombophilia assay CPT codes (group 1)CPT

85300	Clotting inhibitors or anticoagulants; antithrombin III, activity.
85301	Clotting inhibitors or anticoagulants; antithrombin III, antigen assay.
85302	Clotting inhibitors or anticoagulants; protein C, antigen

Thrombophilia assay CPT codes (group 2)CPT

85303	Clotting inhibitors or anticoagulants; protein C, activity.
85305	Clotting inhibitors or anticoagulants; protein S, total.
85306	Clotting inhibitors or anticoagulants; protein S, free.
85307	Activated Protein C (APC) resistance assay

inv-14: Timing for plasma testing

Timing for plasma testing>= 6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants.

Assay sequencingAssays for clotting inhibitor amount and function should be performed prior to any molecular (genetic) testing.

Context noteApplies to plasma testing for protein C, protein S, and antithrombin III deficiencies as noted in policy notes.

Provider requirements, ordering guidance, and operational notes

Prior Authorization

Prior Authorization — Not Specified

Prior authorization: The source policy sections do not specify any prior authorization (PA) requirement for thrombophilia testing. Providers should verify member benefit coverage and PA requirements with Blue Cross Blue Shield of Tennessee prior to ordering, as PA rules (if any) are dependent on the individual’s plan and are not stated in this policy.

No prior authorization language is present in the policy text — confirm plan-level PA requirements before ordering.

Documentation Required

Timing / Prior Authorization Considerations

Timing relative to anticoagulation and initial therapy: Defer thrombophilia testing until after completion of initial anticoagulant therapy when possible. Where testing of plasma-based clotting inhibitors (protein C, protein S, antithrombin) is indicated, perform these assays at least six weeks after the acute thrombotic event and only when the patient is not taking anticoagulants. For genetic testing and other assays, many guidelines recommend waiting a minimum of 3 months after the VTE event or after completion of the initial 3-month anticoagulation course unless results would immediately change management — document the clinical rationale and timing in the chart when testing is performed earlier.

How and when to order tests

Note

Run inhibitor amount/function assays before molecular testing

Perform clotting inhibitor amount and function assays prior to any molecular testing, and ensure timing considers the acute event (wait until after the acute phase and off anticoagulants).

Assays for clotting inhibitors amount/function should be completed before molecular/genetic testing for thrombophilia.

Documentation Required

Order tests only if results will change management; document timing and rationale

Order thrombophilia tests only when results will impact clinical management; ensure testing is timed off anticoagulation and after acute events, and document the clinical rationale (age, site, recurrence, family history).

Do not perform testing at time of VTE or while on anticoagulation; document indication and timing relative to therapy completion.

Documentation Required

Ensure LDTs have in-house CLIA validation

Testing frequency and repeat intervals

inv-43: protein C/protein S/antithrombin III

Frequency for protein C/protein S/antithrombin IIINot specified in the document.

ImplicationNo explicit repeat interval or periodic monitoring frequency is provided for these plasma inhibitor assays.

Related guidanceTiming guidance for initial testing (post-acute and off anticoagulants) is provided elsewhere in policy.

inv-44: Protein levels, homocysteine, factor VIII

Repeat timing for non-DNA protein testing (general)Repeat non-DNA protein or homocysteine testing after the acute phase when adult levels have been attained or after 4–6 weeks.

Factor VIII specificFactor VIII may require repeat testing up to 6 months after the acute event before results are reliable.

Key definitions and test descriptions

inv-32: VTE / Thrombophilia definitions

VTE definitionVenous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

Thrombophilia definitionThrombophilias are hereditary and/or acquired abnormalities of hemostasis that predispose patients to thrombosis.

Common presentationsThe most common presentations of VTE are DVT and PE.

inv-33: aPC resistance assay

aPC resistance assay descriptionA modified aPTT functional assay that detects resistance to activated protein C (aPC) and was historically used as a screen for Factor V Leiden.

LimitationsFunctional aPC resistance assays can give misleading results in certain settings (e.g., lupus anticoagulant present) and may be affected by anticoagulant therapy.

Clinical background and rationale

Background: Thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE), can result from inherited or acquired thrombophilias. Common inherited risk factors include Factor V Leiden and prothrombin G20210A variants and deficiencies of protein C, protein S, and antithrombin; acquired risks include surgery, immobilization, malignancy, pregnancy, and certain medications.

The policy emphasizes that testing utility depends on clinical context and timing: many assays are influenced by the acute clotting event or by anticoagulant therapy, and routine testing in unselected patients generally does not change management. Targeted testing is recommended for young patients with unprovoked VTE, thrombosis at unusual sites, recurrent events, a strong family history, or when results would directly alter clinical decisions.