CurrentPremera BluecrossPolicy M2041

15.01.047 Venous and Arterial Thrombosis Risk Testing

Defines when venous thrombosis risk testing (plasma assays for protein C, protein S, antithrombin III, genetic testing for Factor V Leiden and Prothrombin G20210A, and related tests) is considered reimbursable or not reimbursable and provides related testing/timing notes and guideline context.

Policy Summary

PayerPremera Bluecross

Policy15.01.047 Venous and Arterial Thrombosis Risk Testing

Policy CodePolicy M2041

Change TypeNew policy (approved Oct 14, 2025)

Effective DateFeb. 6, 2026

Next Review DateOct 14, 2025

Key ActionDocument clinical indication meeting one of the reimbursable criteria and ensure plasma testing is performed at least six weeks after the acute thrombotic event and while the patient is not on anticoagulants.

SourceLink

POLICY UPDATE CHANGES

New policy approved October 14, 2025 and effective for dates of service on or after February 6, 2026 following 90-day provider notification.

8Reimbursable scenarios

3Non-reimbursable scenarios/tests

7Cited CPT codes

multipleGuideline sources cited

Coverage Summary

Policy M2041 (Venous and Arterial Thrombosis Risk Testing) defines coverage for plasma assays measuring protein C, protein S, and antithrombin III, genetic testing for Factor V Leiden (FVL) and Prothrombin G20210A, and related risk testing (including antiphospholipid antibodies, JAK2, and evaluation for paroxysmal nocturnal hemoglobinuria in select scenarios). The policy takes a mixed coverage stance — listing specific reimbursable indications for plasma and genetic thrombophilia testing while excluding several situations and tests — and includes operational timing and specimen notes. New policy approved October 14, 2025 and effective for dates of service on or after February 6, 2026 following 90-day provider notification. (Policy number: M2041.)

Key thresholds / testing timing

Plasma testing timing after acute event>= 6 weeks after acute thrombotic event and while not taking anticoagulants (perform assays prior to molecular testing)

Waiting period after anticoagulation completionMinimum 3 months after finishing anticoagulant therapy before certain thrombophilia tests OR use a staged approach; ACC alternatives: wait 2 weeks after stopping warfarin or 2 days after stopping DOACs/heparin for select assays

Age threshold for select genetic testingConsider genetic testing (e.g., FVL, prothrombin G20210A) for first unprovoked VTE at young age — guideline trigger often <45 years (policy notes <45 and multiple guidelines cite <50)

Wells score threshold for PEWells score >= 4.5 = PE likely → proceed to imaging; do not use D-dimer to rule out PE when Wells >= 4.5

Age-adjusted D-dimer cutoffFor patients >50 years: negative if D-dimer < (age × 10) µg/L; for patients <50 years: cutoff 500 µg/L

Policy lists 8 reimbursable clinical scenarios for protein testing and 3 explicitly non-reimbursable scenarios/tests (per internal stats). The policy contains clear reimbursable indications (e.g., age <50 with DVT/PE, unusual-site DVT, strong family history, pregnancy/OC-related DVT, neonatal purpura fulminans, warfarin-induced skin necrosis) and specific not-reimbursable items (e.g., superficial venous thrombosis, activated protein C resistance assay, pre-transplant DVT risk testing). Operational notes require plasma testing timing and specimen handling guidance (see timing and assay-before-genetic-testing requirements).

Medically Reimbursable and Exclusion Criteria

Medically Reimbursable Indications (protein C/S/antithrombin plasma testing)

Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency is considered reimbursable when ANY of the following are met:

ANY of the following

Individuals < 50 years who have experienced any deep venous thrombosis (DVT) or pulmonary embolism (PE).
Individuals who have experienced a DVT in unusual sites (e.g., hepatic, mesenteric, or cerebral veins).
Individuals who have experienced a DVT and who have a strong family history of thrombotic disease.
Individuals who are pregnant or taking oral contraceptives and who have experienced a DVT.
First- and second-degree relatives of individuals who experienced a DVT before 50 years of age.
Women under the age of 50 who smoke and who have suffered a myocardial infarction.
Before the administration of oral contraceptives, targeted testing of individuals with a personal or family history of DVT.
Pediatric individuals who have suffered from a pediatric arterial ischemic stroke.

Note: Assays should be performed at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants. Assays for clotting inhibitors amount and function should be performed prior to any molecular testing.

Operational timing

Medically Reimbursable Indications (special situations)

Plasma testing for protein C deficiency and protein S deficiency is considered reimbursable when ANY of the following special situations are present:

ANY of the following

Infants who develop neonatal purpura fulminans.
Individuals with warfarin-induced skin necrosis.

Note: These indications apply specifically to plasma testing for protein C and protein S.

Clinical scope

Not Reimbursable

Testing considered not reimbursable in the following circumstances:

ANY of the following

Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities).
Activated protein C (aPC) resistance assay (APC resistance assay).
DVT risk testing as part of a pre-transplant evaluation.

Note: aPC resistance assays are not reimbursable in all situations regardless of clinical context.

Policy exclusion

Reimbursable Indications (summary from policy addition)

Reimbursable indications summarized from policy additions — ANY of the following support testing or related evaluation:

ANY of the following

Antepartum or postpartum prophylaxis planning for individuals with prior thrombosis or high-risk thrombophilia where results would change management.
Testing and evaluation for antiphospholipid antibodies, JAK2 mutation, or paroxysmal nocturnal hemoglobinuria (PNH) when clinically suspected and results will affect treatment.
Assessment of cancer patients with thrombosis when results would influence anticoagulation strategy or diagnostic evaluation.
Testing to inform counseling on estrogen-containing medications, pregnancy management, or hormone replacement therapy when a personal or strong family history of VTE exists.

Not Routinely Recommended / Not Reimbursable (per guideline consensus reflected in policy)

Guideline-consensus–based recommendations reflected in this policy — ALL of the following are considered not routinely recommended or not reimbursable:

ALL of the following

Do not perform thrombophilia testing for individuals with arterial thrombosis (including myocardial infarction and stroke) for the purpose of explaining the arterial event.
Do not perform activated protein C (aPC) resistance assays as a routine thrombophilia test; preferentially use genetic testing for Factor V Leiden when indicated.
Do not perform broad thrombophilia panels in patients where results will not change acute management or anticoagulation duration (for example, provoked VTE due to transient major risk factors).
Do not perform routine thrombophilia testing as part of preoperative or pre-transplant evaluations unless specific clinical indications exist that would alter management.

Timing, Specimen, and Testing Sequence

Timing and specimen requirements (operational notes)

ALL of the following

Patient should not be taking anticoagulants at time of testing.
operational note
Plasma testing for protein C, protein S, and antithrombin III should be performed at least six weeks after the acute thrombotic event.>= 6 weeks
operational note
Assays for clotting inhibitors amount and function should be performed prior to any molecular (genetic) testing.
operational note

Testing interpretation is affected by anticoagulants and acute events; plasma assays for protein C, protein S, and antithrombin III should be performed at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants, and assays of inhibitor amount/function should be done prior to molecular testing. Guideline alternatives for timing include waiting a minimum of 3 months after completion of anticoagulant therapy (or staged testing) for certain evaluations; ACC guidance notes alternative shorter waits for testing after stopping therapy (for example, about 2 weeks after stopping warfarin or 2 days for DOACs or heparin for select assays), but testing during anticoagulation or in the acute phase may give inaccurate results.

Provider Actions / Billing Impact

Documentation Required

Confirm indication and timing for plasma testing

Document the clinical indication demonstrating the patient meets one of the reimbursable criteria for plasma testing (e.g., age <50 with DVT/PE, DVT at an unusual site, strong family history, pregnancy or OC-associated DVT, first- or second-degree relatives of early DVT cases, pediatric arterial ischemic stroke, warfarin-induced skin necrosis, neonatal purpura fulminans). Ensure plasma assays for protein C, protein S, and antithrombin III (CPT 85300, 85301, 85302, 85303, 85305, 85306) are performed at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants.

Affected CPT codes: 85300, 85301, 85302, 85303, 85305, 85306
Document which reimbursable indication is met (see policy indications)
Document testing occurs >= 6 weeks after acute event and while off anticoagulants

Denial Risk

Claims likely not reimbursable for excluded indications

Claims for testing using the activated protein C (aPC) resistance assay (CPT 85307) and for thrombosis risk testing in excluded settings (superficial venous thrombosis including superficial thrombophlebitis/varicosities, and DVT risk testing as part of pre-transplant evaluation) are not reimbursable and may be denied.

Affected CPT code: 85307
Excluded indications: superficial venous thrombosis (including superficial thrombophlebitis and varicosities), aPC resistance assays, DVT risk testing for pre-transplant evaluation

Documentation Required

Perform clotting inhibitor assays before molecular testing

Perform and document assays for clotting inhibitor amount and function (protein C, protein S, antithrombin III) before ordering molecular/genetic testing. Record the assay results in the medical record prior to requesting genetic tests for Factor V Leiden or prothrombin G20210A.

Document assay results prior to ordering genetic tests (e.g., FVL, prothrombin G20210A)

Prior Authorization

Reimbursement consideration requires meeting policy indications

Venous and arterial thrombosis risk testing is considered for reimbursement only when the clinical indications enumerated in the policy are met. For reimbursement consideration, document which policy indication applies and provide a clear explanation of how the test result is expected to change patient management or prophylaxis decisions.

Document how test results will change management (e.g., influence thromboprophylaxis, family testing, or duration of anticoagulation)

Documentation Required

Document family/personal history and intent to change management

Document personal and family history elements required to support testing and to show potential impact on care. Capture the degree of relationship (first- or second-degree), whether a known familial high-risk thrombophilia is present (e.g., antithrombin, protein C, protein S deficiency, homozygous FVL, combination FVL+PGM), and specifically state what management or prophylaxis decisions would change based on test results.

Relationship degree (first- or second-degree relative)
Known familial thrombophilia (specify type if known)
Planned change in management or prophylaxis if test positive

Denial Risk

Claims risk for routine or inappropriate testing

Claims for routine or inappropriate thrombophilia testing in settings the policy and guidelines list as not recommended are at risk for denial. Examples include testing after provoked VTE, routine testing of asymptomatic relatives when results would not change management, and testing during an acute VTE or while the patient is receiving anticoagulation therapy.

Likely denied scenarios: provoked VTE testing; asymptomatic relatives without intended management changes; testing during acute VTE or while on anticoagulants

Billing Rule

Policy applies to routine test management reimbursement

This policy is a guide for Company staff in determining coverage and reimbursement methodology for routine thrombosis risk testing. Coverage and reimbursement remain subject to the member's specific benefit limits and plan terms; verify member benefits or contact member services for plan-specific coverage determinations.

Coverage and reimbursement depend on member benefit limitations and plan terms
Policy guides Company staff decisions but does not override member contract

Background, Evidence, and Definitions

Thrombosis occurs when a blood clot obstructs a vein (venous thrombosis; e.g., DVT, PE) or an artery (arterial thrombosis). Thrombophilias are hereditary or acquired abnormalities that increase thrombotic risk. Common hereditary risk factors include Factor V Leiden, prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin. Testing utility is limited in many settings — especially in children, for most arterial thrombosis presentations, and when results are unlikely to change management — because penetrance is low and most carriers never develop thrombosis; routine testing often does not alter acute management.

Evidence	Findings/Notes
Systematic review (Chiasakul et al. 2019)
Found associations between inherited thrombophilias and arterial ischemic stroke: FVL OR 1.25; prothrombin G20210A OR 1.48; protein C deficiency OR 2.13; protein S deficiency OR 2.26; antithrombin deficiency not significant.
Analytical concordance (Murphy & Sabath 2019)
Phenotypic aPC resistance assays had close to total concordance with genotypic assays over 16 years; potential testing cost reductions and high sensitivity/specificity versus genotyping.
Guideline consensus
Multiple organizations (ACMG, ASH, ACOG, ACC, NICE, Anticoagulation Forum) recommend limited/thoughtful use of thrombophilia testing: generally avoid routine testing in provoked VTE and asymptomatic relatives; defer testing during acute events or while on anticoagulation; testing may be appropriate in select scenarios (young age, unusual sites, family history) and timing matters.
EGAPP recommendation
Recommend against routine testing for FVL and prothrombin 20210G>A in adults with idiopathic VTE and asymptomatic adult family members for primary prophylaxis consideration.

Term	Definition
First-degree relatives
Parents, full siblings, and children of the individual.
Second-degree relatives
Grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings of the individual.
High-risk thrombophilia
Includes antithrombin deficiency, protein C deficiency, protein S deficiency, homozygous Factor V Leiden, or combination of FVL and prothrombin G20210A mutation as referenced in guideline summaries.
Provoked VTE
Venous thromboembolism associated with transient risk factors such as surgery, immobilization, trauma, concurrent cancer diagnosis, or concurrent hormone use.

OpenPayer

15.01.047 Venous and Arterial Thrombosis Risk Testing

Coverage Summary

Medically Reimbursable and Exclusion Criteria

Timing, Specimen, and Testing Sequence

Provider Actions / Billing Impact

Codes

Background, Evidence, and Definitions

Revision History

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.
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.