ModifiedMolina HealthcarePolicy M2041

Venous and Arterial Thrombosis Risk Testing

Defines clinical coverage criteria and limitations for laboratory and genetic testing to assess venous and arterial thrombosis (thrombophilia) risk, including indications when various tests meet coverage criteria or do not meet coverage criteria and timing/notes for testing.

Policy Summary

PayerMolina Healthcare

PolicyVenous and Arterial Thrombosis Risk Testing

Policy CodePolicy M2041

Change TypeRevision (header updated; literature reviewed)

Effective Date

Next Review Date

Key ActionEnsure plasma testing for protein C, protein S, and antithrombin III is performed at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants; perform assays of amount and function prior to molecular testing.

POLICY UPDATE CHANGES

Revision date listed as 07/01/2025 in header.

Reviewed and Updated: Updated the background, guidelines and recommendations, and evidence-based scientific references.

8Covered Indications

3Explicit Exclusions

MultipleGuideline Sources

7CPT codes listed

Conditional

Most recommendations

Coverage Summary

Scope: This policy (M2041) defines clinical coverage criteria and limitations for laboratory and genetic testing to assess risk of venous and arterial thrombosis (thrombophilia), including which tests and clinical scenarios meet coverage and which do not meet coverage, plus timing and documentation requirements.

Coverage stance: Mixed — some plasma and genetic tests (e.g., plasma testing for protein C, protein S, and antithrombin III in specified clinical situations; MTHFR testing in pediatric arterial ischemic stroke <21) meet coverage criteria, while specific assays and routine screenings (e.g., aPC resistance assay, superficial venous thrombosis risk testing, DVT pre-transplant evaluation, routine population screening) do not meet coverage criteria.

High-level guidance: Follow specific scenario-based indications (e.g., age <50 with DVT/PE, unusual-site DVT, strong family history, pregnancy/oral contraceptive–associated DVT, first- or second-degree relatives of DVT before age 50, pediatric arterial ischemic stroke) and timing rules — perform plasma assays at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants; document the indication and how results will change management. Verify individual benefit coverage and applicable government LCD/NCDs.

Key thresholds and policy metadata

policy_numberM2041

last_review2025-07-01

Timing after acute thrombotic event for plasma testingAt least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants

ACMG timing for deferring repeat testing after strokeDeferred or repeated at least 4 to 6 weeks (or up to 6 months for factor VIII) after the acute stroke

Wells score threshold for PEPE unlikely if <4.5; PE likely if >=4.5

Age-adjusted D-dimer cutoff (Thrombosis Canada)Negative if < (patient age x 10) µg/L for patients >50; <500 µg/L for patients <=50

scope_summaryDefines clinical coverage criteria and limitations for laboratory and genetic testing to assess venous and arterial thrombosis (thrombophilia) risk, including indications when various tests meet coverage criteria or do not meet coverage criteria and timing/notes for testing.

Medical-Necessity Criteria

Plasma testing for protein C, protein S, and antithrombin III deficiency - Medically Necessary

Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency is MEDICALLY NECESSARY when ANY of the following clinical situations are present:

ANY of the following

Individual <50 years of age who has experienced any deep venous thrombosis (DVT) or pulmonary embolism (PE).
Individual who has experienced a DVT in unusual sites (e.g., hepatic, mesenteric, or cerebral veins).
Individual who has experienced a DVT and who has a strong family history of thrombotic disease.
Individual who is pregnant or taking oral contraceptives and who has experienced a DVT.

Not Covered / Testing Limitations

Activated protein C (aPC) resistance assay - Not Covered

aPC resistance assay coverage stance:

Activated protein C (aPC) resistance assay DOES NOT MEET COVERAGE CRITERIA

Venous thrombosis risk testing for superficial venous thrombosis - Not Covered

Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities) DOES NOT MEET COVERAGE CRITERIA

DVT risk testing as part of pre-transplant evaluation - Not Covered

DVT risk testing as part of a pre-transplant evaluation test DOES NOT MEET COVERAGE CRITERIA

Guideline-based exclusions and routine testing limitations: multiple guideline bodies recommend against routine or untargeted thrombophilia testing. EGAPP recommends against routine Factor V Leiden and prothrombin 20210G>A testing in adults with idiopathic VTE and in asymptomatic adult family members.

When Testing May Be Considered / Recommended

Selected scenarios where testing may be beneficial per guideline bodies

Selected scenarios where testing may be beneficial per guideline bodies:

ANY of the following

Testing may be considered in adults with a first unprovoked VTE at a young age (e.g., <45 years) or unusual site to inform genetic counseling or specific management (ACC).
Consider testing for antiphospholipid antibodies in people with unprovoked DVT/PE if planned to stop anticoagulation (NICE; ACC: may guide extended anticoagulation decisions).
For women with a first-degree family history of high-risk thrombophilia (homozygous FVL, combination FVL+PGM, antithrombin deficiency, protein C or S deficiency), ASH suggests testing for the known familial thrombophilia to guide antepartum/postpartum thromboprophylaxis (conditional, very low certainty).

Operational Timing and Testing Considerations

Operational timing and testing considerations

Guidance about timing and interpretation of tests:

Do not perform thrombophilia testing during an acute VTE event or while on anticoagulation due to spurious results; wait at least 3 months after anticoagulation course or after holding anticoagulation (Anticoagulation Forum; ACC).

When testing following VTE, use either a 2-stage testing approach or perform testing after a minimum of 3 months of anticoagulant therapy has been completed and anticoagulants have been held (Anticoagulation Forum).

Some tests (antiphospholipid antibodies, protein C/S, antithrombin) can be affected by anticoagulants and may require specialist advice (NICE; ACC).

Provider Actions & Billing Impact

Prior Authorization

Prior authorization may be required per payer policy (implied)

Verify the patient's benefits and whether prior authorization (PA) is required with the payer before ordering testing. Coverage determinations should follow the plan's criteria and any applicable government LCDs/NCDs.

Check member-specific benefit coverage and PA rules before testing.
Confirm applicability of local or national Medicare/Medicaid coverage (LCD/NCD) if relevant.

Prior Authorization

Apply coverage criteria based on individual benefits

Apply the coverage criteria based on the individual's benefit coverage at the time of the request. Verify Medicare and Medicaid specifications in the policy's Applicable State and Federal Regulations section when relevant to the member.

Coding

Applicable CPT codes for thrombophilia-related lab testsCPT

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

Background & Evidence Summary

Background: Thrombosis (blood clotting within vessels) occurs as venous thrombosis (vein occlusion) or arterial thrombosis (artery occlusion). The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) and pulmonary embolism (PE).

Thrombophilias encompass hereditary and acquired abnormalities that predispose to thrombosis. Common inherited risk factors include Factor V Leiden (FVL), prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin. Acquired risk factors include prior VTE, surgery, immobilization, malignancy, pregnancy, oral contraceptive use, antiphospholipid syndrome, and others.

Guideline perspectives and analytic/clinical validity: Professional societies (ACC, ASH, ACOG, ACMG, AHA/ASA, NICE, Anticoagulation Forum, WHO) provide nuanced guidance: testing is appropriate in selected scenarios (young age at first unprovoked VTE, unusual sites, strong family history, certain peripartum decisions) but not recommended routinely. Analytical studies report high concordance between genotypic and phenotypic assays for FVL (phenotypic aPC resistance assays showed close to total concordance with genotypic assays over 16 years), while evidence for clinical utility to change outcomes is limited; genetic tests are analytically valid but clinical utility is often conditional or low certainty.

Selected evidence highlights

Analytical concordancePhenotypic aPC resistance assays had close to total concordance with genotypic assays over 16 years (Murphy & Sabath 2019)

Systematic review finding

Definitions

Term	Definition
aPC	Activated protein C
DVT	Deep vein thrombosis
PE	Pulmonary embolism
VTE	Venous thromboembolism
High-risk thrombophilia	Antithrombin deficiency, protein C deficiency, protein S deficiency, homozygous FVL, combination of FVL and PGM (per ASH/ACOG context)

Revision History

06/16/2015initial_presentation

Document header shows Initial Presentation Date 06/16/2015.

07/01/2025revisionLatest

Revision date listed as 07/01/2025 in header. Reviewed and Updated: Updated the background, guidelines and recommendations, and evidence-based scientific references. Literature review did not necessitate any modifications to coverage criteria.

Policy Summary

PayerMolina Healthcare

PolicyVenous and Arterial Thrombosis Risk Testing

Policy CodePolicy M2041

Change TypeRevision (header updated; literature reviewed)

Effective Date

Next Review Date

On This Page

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.

Targeted testing before the administration of oral contraceptives for individuals with a personal or family history of DVT.

Pediatric individuals who have suffered from a pediatric arterial ischemic stroke.

Plasma testing for protein C and protein S deficiency - Medically Necessary (specific)

Plasma testing for protein C deficiency and protein S deficiency is MEDICALLY NECESSARY in the following specific situations:

ANY of the following

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

MTHFR genetic testing - Medically Necessary

MTHFR genetic testing is MEDICALLY NECESSARY when ALL of the following are present:

ALL of the following

Pediatric arterial ischemic stroke has occurred.
Individual age < 21 years.

When thrombophilia testing is NOT recommended

When thrombophilia testing is NOT recommended:

ANY of the following

Activated protein C (aPC) resistance assay — DOES NOT MEET COVERAGE CRITERIA.
Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities) — DOES NOT MEET COVERAGE CRITERIA.
DVT risk testing as part of a pre-transplant evaluation — DOES NOT MEET COVERAGE CRITERIA.

Anticoagulation Forum and NICE advise not to perform thrombophilia testing after a provoked VTE; testing following unprovoked VTE is discouraged unless results would change duration of anticoagulation, and testing should not be done during the acute event or the initial 3-month course of anticoagulation.

ACC and Anticoagulation Forum emphasize that testing during acute VTE or while on anticoagulation yields spurious results and should be deferred until after anticoagulation has been held (Anticoagulation Forum; ACC). NICE specifically advises not to offer hereditary thrombophilia testing to people who are continuing anticoagulation treatment and not to routinely offer testing to first-degree relatives.

WHO and other sources state that population-level routine screening is not appropriate because these thrombogenic conditions are rare and screening is costly. ACOG and ACMG advise against testing for MTHFR polymorphisms or fasting homocysteine for thrombophilia assessment.

For ambulatory cancer patients receiving systemic therapy with a family history of VTE and otherwise low/intermediate VTE risk, ASH suggests testing for hereditary thrombophilia; provide ambulatory thromboprophylaxis if thrombophilia present (conditional, very low certainty).

For women considering estrogen use with a first-degree relative with VTE and known hereditary thrombophilia, test for that thrombophilia if the result would change decision to use estrogen (Anticoagulation Forum).

Among women with personal histories of VTE, recommended screening tests include FVL mutation; prothrombin G20210A mutation; antithrombin, protein S, and protein C deficiencies (ACOG consensus/expert opinion).

For women with family history of VTE and known high-risk thrombophilia, ASH suggests avoidance of COCs or HRT (conditional, very low certainty) and testing when known familial high-risk thrombophilia present.

For certain familial thrombophilias (homozygous FVL, combination FVL+PGM, antithrombin deficiency), ASH suggests antepartum or postpartum thromboprophylaxis for women with the same familial thrombophilia and no prophylaxis for women without it (conditional).

Documentation Required

Timing and anticoagulant status for plasma assays

Perform plasma testing for protein C, protein S, and antithrombin III at least six weeks after the acute thrombotic event and only when the patient is not taking anticoagulants. In addition, perform assays of both amount and function for these clotting inhibitors prior to any molecular (genetic) testing.

Wait a minimum of six weeks after the acute thrombotic event before plasma testing.
Ensure the patient is not on anticoagulant therapy at the time of plasma assays.
Perform assays of clotting inhibitor amount and function before ordering molecular/genetic testing.

Determine coverage eligibility using the member's current benefit plan.
Refer to the Applicable State and Federal Regulations section for Medicare/Medicaid specifics.

Documentation Required

Family relationship documentation

When testing is based on family history, document the relationship using Note 3 definitions. First-degree relatives include parents, full siblings, and children. Second-degree relatives include grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.

First-degree: parents, full siblings, children.
Second-degree: grandparents, aunts, uncles, nieces, nephews, grandchildren, half-siblings.

Documentation Required

Document clinical indication and how test result will change management

Document the clinical indication for thrombophilia testing and explicitly state how the test result would change patient management (for example, influence contraceptive decisions, anticoagulation duration, or peri‑pregnancy prophylaxis).

Record the precise clinical scenario prompting testing (e.g., young unprovoked VTE, unusual site, family history).
State the management decision that would be altered by a positive or negative result.

Denial Risk

Risk of denial for inappropriate timing

Claims for thrombophilia testing performed during an acute VTE event or while the patient is on anticoagulation, or for routine/asymptomatic screening, may be denied. To reduce denial risk, ensure appropriate timing (after anticoagulation held) and that testing is medically necessary per plan criteria.

85300
85301
85302
85303
85305
85306
85307

Inherited thrombophilias associated with increased risk of arterial ischemic stroke (ORs: FVL 1.25; Prothrombin 1.48; Protein C 2.13; Protein S 2.26) (Chiasakul 2019)

ASH 2023 guidelineConditional recommendations on thrombophilia testing; very low certainty evidence

EGAPP 2011Recommend against routine FVL/PT testing in adults with idiopathic VTE and asymptomatic adult family members