Venous and Arterial Thrombosis Risk Testing
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Policy governing coverage and limitations for laboratory testing to evaluate inherited and acquired thrombophilias and related assays for venous and arterial thrombosis risk; applies to Blue Cross and Blue Shield of Louisiana members and providers requesting such testing.
Removal of CC1.f. from coverage criteria following ACMG guideline update.
Former CC1.d. edited for clarity.
Removed assays timing note: 'Assays for clotting inhibitors amount and function should be performed prior to any molecular testing.'
Removed CPT codes 81240, 81241, 81291, 81400, 81479, 0278U from the policy's code list.
New CC6: activated protein C (aPC) resistance assay DOES NOT MEET COVERAGE CRITERIA.
Coverage Criteria
inv-01: Covered — Protein C, Protein S, Antithrombin III
Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency MEETS COVERAGE CRITERIA when ANY one of the following applies:
inv-02: Covered — Special clinical presentations
Specific covered situations (separate):
inv-04: ACMG — Recommended testing indications for Factor V Leiden and prothrombin G20210A
ACMG: Testing for Factor V Leiden and prothrombin G20210A is recommended when any of the following applies:
From ACMG guidance
inv-05: ACMG — Suggested testing indications
ACMG: Testing is suggested (may be considered) in these scenarios:
From ACMG guidance
inv-06: AHA/ASA — Pediatric and timing guidance
AHA/ASA: Recommendations regarding testing timing and pediatric considerations
inv-07: ASH — Testing recommendations and limitations
ASH: Recommendations on who to test and when (multiple conditional recommendations based on very low certainty)
Multiple ASH conditional recommendations
From ASH guidance
inv-08: ACOG — Obstetric screening guidance
ACOG: Recommendations on screening in obstetric contexts
ACOG 2018
ACOG 2018 consensus
inv-09: Coverage criteria revisions (summary) — revision notes
Review/Revision History notes changes to coverage criteria (summary):
See Review/Revision History for dates and rationale.
Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities) DOES NOT MEET COVERAGE CRITERIA and is excluded from coverage.
Activated protein C (aPC) resistance assay is explicitly listed as excluded: the policy states that the aPC resistance assay DOES NOT MEET COVERAGE CRITERIA, and this exclusion is recorded as new criterion CC6 in the Review/Revision History.
Testing to assess deep vein thrombosis (DVT) risk as part of a pre-transplant evaluation is excluded because available published literature does not demonstrate that such testing is required or beneficial; therefore, pre-transplant DVT risk testing DOES NOT MEET COVERAGE CRITERIA.
Prenatal testing and population screening for common thrombophilia variants are not indicated; the ACMG advises that prenatal testing and population screening are not recommended due to low penetrance, later age of onset, and lack of genotype-directed prophylaxis. Testing for MTHFR variants is not supported for thrombophilia assessment because it lacks correlation with adverse pregnancy outcomes.
The policy explicitly records in the Review/Revision History (new CC6) that an aPC resistance assay DOES NOT MEET COVERAGE CRITERIA. Claims for this assay may be denied under the policy because it is not a covered service.
Routine thrombophilia testing in clinical settings where there is no evidence that results will change management is not covered. Examples include routine pediatric testing without clinical indication and other situations lacking demonstrated benefit; such routine use is considered not medically necessary or does not meet coverage criteria.
Routine thrombophilia testing to guide broad population decisions (for example, screening average-risk women prior to initiating combined oral contraceptives or hormone replacement therapy) is not recommended and is not supported by guideline bodies; thus such routine population-level screening is not covered.
The policy designates the aPC resistance assay as not meeting coverage criteria (CC6). As such, use of the functional aPC resistance assay is considered not medically necessary for coverage under this policy.
Covered Indications
inv-41: Protein C, protein S, and antithrombin III plasma testing — covered with timing/specimen notes
Plasma testing for protein C, protein S, and antithrombin III deficiency MEETS COVERAGE CRITERIA when ANY one of the listed indications is met; specimen timing and anticoagulant status requirements apply:
inv-42: Protein C and protein S testing — warfarin-induced skin necrosis or neonatal purpura fulminans
inv-43: Testing for Factor V Leiden and prothrombin G20210A — covered per ACMG/selected ASH scenarios
Testing for Factor V Leiden and prothrombin G20210A MEETS COVERAGE CRITERIA when ACMG-recommended indications are present:
Per ACMG guidance
Per ASH guidance
inv-44: Thrombophilia panel testing to guide anticoagulation duration
Thrombophilia panel testing to inform anticoagulation duration is covered in select scenarios per ASH conditional recommendations:
ASH conditional recommendations
ASH guidance
inv-45: Thrombophilia evaluation in contexts referenced by guideline bodies
Thrombophilia evaluation is covered in contexts referenced by guideline bodies and noted in the policy revision history:
Not Covered / Exclusions
Not covered under this policy are: aPC resistance assays; testing to assess venous thrombosis risk for superficial venous thrombosis (including superficial thrombophlebitis and varicosities); and DVT risk testing performed as part of pre-transplant evaluations.
The policy does not support routine MTHFR variant testing and advises against prenatal or population screening for common thrombophilia variants because these approaches lack clinical utility and do not inform genotype-directed prophylaxis.
The activated protein C (aPC) resistance assay is explicitly stated as not meeting coverage criteria (CC6) in the policy and is therefore listed as not covered.
Coding and Procedure Codes
| No codes listed |
| 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. |
| 81240 | Removed from policy code list (previous genetic test code). |
| 81241 | Removed from policy code list (previous genetic test code). |
| 81291 | Removed from policy code list (previous genetic test code). |
| 81400 | Removed from policy code list (previous genetic test code). |
| 81479 | Removed from policy code list (previous genetic test code). |
| 0278U | Removed from policy code list (removed 09/01/2023). |
Provider Actions and Prior Authorization
Clinical indication requirement — order only for listed indications
Coverage for thrombophilia testing is limited to the clinical indications listed in the policy. Order plasma testing for protein C, protein S, and antithrombin III only when one of the covered scenarios applies (for example: individuals <50 years with DVT or PE; DVT at unusual sites such as hepatic, mesenteric, or cerebral veins; DVT with a strong family history; DVT in pregnancy or while taking oral contraceptives; first- or second-degree relatives of someone with DVT before age 50; targeted testing before OCs when there is a personal or family history of DVT; pediatric arterial ischemic stroke).
- Covered indications include: age <50 with DVT/PE; unusual-site DVT; strong family history of thrombotic disease; pregnancy or OC-associated DVT; first- and second-degree relatives of early-onset DVT; targeted pre-OC testing for those with personal/family DVT history; pediatric arterial ischemic stroke.
- Special coverage: plasma testing for protein C and protein S meets criteria for warfarin-induced skin necrosis and neonatal purpura fulminans.
Prior authorization for non-indicated thrombophilia testing
Prior authorization may be required when thrombophilia testing is requested outside the policy’s recommended indications (for example, asymptomatic population screening or prenatal screening). Requests for tests outside specified clinical scenarios may not meet coverage criteria.
- Policy emphasizes testing only in specified scenarios and notes routine/population or prenatal screening is not indicated.
- Prior auth may be used to manage non-indicated requests.
Procedure code considerations — use listed CPT codes on requests
When submitting claims or prior authorization requests, reference the policy’s listed CPT procedure codes for plasma clotting inhibitor and protein testing; prior authorization or billing guidance should use these codes when applicable.
- Example CPT codes listed: 85300 (ATIII activity), 85301 (ATIII antigen), 85302 (Protein C antigen), 85303 (Protein C activity), 85305 (Protein S total), 85306 (Protein S free), 85307 (APC resistance assay).
- Note: policy revision removed several CPT/genetic codes in prior updates per the Review/Revision History.
Ordering sequence & timing — defer testing ≥6 weeks and off anticoagulants
Do not order protein C, protein S, or antithrombin III plasma testing during the acute thrombosis phase; collect specimens at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants when possible.
- Note 1: perform plasma testing ≥6 weeks after the acute thrombotic event and while the patient is not taking anticoagulants.
- Timing guidance aligns with covered-indication language requiring deferred testing after an acute event.
D-dimer as initial step — follow positive result with imaging
Use D-dimer as the initial step to exclude PE or DVT in populations with appropriate pretest probability per ASH recommendations; a positive D-dimer should prompt imaging (eg, CTPA or VQ for PE; proximal/whole-leg ultrasound for DVT) rather than being used alone to establish diagnosis.
- ASH recommends starting with D-dimer to exclude PE or DVT in low or intermediate pretest probability populations, followed by imaging for patients requiring additional testing.
- ASH recommends against using a positive D-dimer alone to diagnose PE or DVT.
Step therapy — no additional step therapy rules specified
The policy excerpt does not specify any step therapy rules for thrombophilia testing beyond timing and sequencing guidance; there are no additional mandated step interventions listed.
- Review/Revision History and step therapy modules state no formal step therapy rules are specified in this excerpt.
Timing & specimen conditions — collect ≥6 weeks post-event and off anticoagulants
Specimen timing and conditions must be documented: plasma testing for protein C, protein S, and antithrombin III should be performed at least six weeks after an acute thrombotic event and while the patient is not receiving anticoagulants.
- Ensure the specimen is collected off anticoagulant therapy when feasible and after the recommended waiting period post-event.
Documentation requirement — record clinical scenario and event timing
Document the clinical scenario and timing relative to the acute event when ordering tests: include indication (type of VTE or unusual site), whether VTE was provoked or unprovoked, family history, pregnancy status, and current contraceptive or HRT use, and note the date of the acute event to confirm appropriate deferment interval.
- Guidelines recommend deferring or repeating protein C/S/antithrombin testing 4–6 weeks (or longer for some factors) after acute stroke/event; record timing in documentation.
- Include family history and reproductive/medication status per ACMG and ACOG context when relevant.
aPC resistance assay denial risk — assay does not meet coverage (CC6)
Requests for activated protein C (aPC) resistance assay will be denied because the assay does not meet coverage criteria (CC6); do not submit claims for aPC resistance assay as a covered plasma test under this policy.
- Policy explicitly states: 'For all situations, activated protein C (aPC) resistance assay DOES NOT MEET COVERAGE CRITERIA.'
- Review/Revision History documents introduction of CC6 designating aPC resistance assay as not covered.
Denial triggers — avoid excluded assays and non-covered indications
Denial triggers include requests for testing outside covered indications—examples specifically called out are aPC resistance assay, venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities), and DVT risk testing as part of a pre-transplant evaluation; ordering tests for these indications may result in denial.
- Do not order tests for superficial venous thrombosis risk assessment or as part of pre-transplant evaluation—these do not meet coverage criteria.
- Avoid ordering aPC resistance assay because it is explicitly excluded from coverage.
Ordering Requirements
Order tests consistent with listed indications and timing
Align ordering with the policy's listed clinical indications and ensure timing criteria are met (including deferral until ≥6 weeks after an acute event); targeted testing prior to OC administration is covered when there is a personal or family history of DVT.
- Targeted pre‑OC testing is listed under III.f when personal or family history of DVT exists.
Order tests according to clinician assessment and guideline‑specified scenarios
Order testing based on clinician assessment in the specified clinical scenarios identified by guideline bodies (e.g., VTE history, strong family history, pregnancy or postpartum VTE, OC/HRT considerations, pediatric arterial ischemic stroke); avoid routine screening in asymptomatic individuals.
- ACMG and ACOG recommendations outline appropriate scenarios for testing and contexts where screening is not recommended.
Ensure LDTs are CLIA‑validated and performed in‑house
Laboratory‑developed tests (LDTs) used for thrombophilia testing are CLIA high‑complexity tests that laboratories must validate and perform in‑house; ensure ordered LDTs meet CLIA requirements.
- LDTs are regulated under CLIA '88 as high‑complexity tests and require in‑house validation.
Frequency Limits
Definitions
Background
Thrombosis encompasses both venous events (deep vein thrombosis and pulmonary embolism) and arterial thrombosis. Thrombophilias are hereditary or acquired abnormalities that increase thrombosis risk; common inherited factors include Factor V Leiden, prothrombin G20210A, and deficiencies of protein C, protein S, and antithrombin. Acquired risk factors include surgery, immobilization, malignancy, pregnancy, oral contraceptive use, central venous catheters, and antiphospholipid syndrome. Interpretation of some assays (for example, aPC resistance) can be affected by anticoagulant therapy or the presence of lupus anticoagulant, and genetic confirmation may be required.
Review / Revision History
ACMG guideline update resulted in removal of coverage criterion CC1.f.; former CC1.d. was edited for clarity; editorial removal of a timing note from Note 1.
Policy revisions removed multiple genetic testing coverage criteria and added CC6 declaring activated protein C (aPC) resistance assay DOES NOT MEET COVERAGE CRITERIA; several CPT/genetic codes were removed from the policy code list.
Under CC2 for plasma testing, 'recurrent deep vein thrombosis' was removed as a subcriterion; CPT code 0278U was added earlier in the policy history before its later removal.
Initial policy implementation recorded.
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