What laboratory test can be used to diagnose antiphospholipid syndrome (APS) in a patient without requiring current anticoagulation?

Laboratory Testing for Antiphospholipid Syndrome Without Current Anticoagulation

For patients not on anticoagulation, order anticardiolipin antibodies (aCL) IgG/IgM and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM by ELISA or automated solid-phase assays, as these tests are unaffected by anticoagulation status, unlike lupus anticoagulant testing which requires special handling during anticoagulation. 1

Recommended Testing Panel

First-Line Tests (No Anticoagulation Required)

Anticardiolipin Antibodies (aCL):

• Measure both IgG and IgM isotypes in plasma or serum using solid-phase assays (ELISA or automated systems) 1
• Positivity defined as levels above the 99th percentile of normal controls 1
• Must be β2GPI-dependent to avoid false positives from infections or drug-related antibodies 1

Anti-Beta2 Glycoprotein I Antibodies (aβ2GPI):

• Measure both IgG and IgM isotypes in plasma or serum using solid-phase assays 1
• Positivity defined as levels above the 99th percentile of normal controls 1, 2
• These antibodies are more specific for APS than non-cofactor-dependent tests 1

Lupus Anticoagulant (LA) Testing Considerations

Critical Pitfall: LA testing is severely compromised during anticoagulation therapy and causes false positive or false negative results 1, 3. If the patient requires anticoagulation before testing can be completed:

• Ideally: Perform LA testing 1-2 weeks after discontinuation of vitamin K antagonists (with or without LMWH bridging) 1
• Alternative for DOACs: Use pretest DOAC removal procedures before LA testing 1, 2
• Alternative for VKA: Consider Taipan snake venom time/ecarin time (TSVT/ET), though this lacks 100% sensitivity 1, 2

When LA testing IS feasible (patient not anticoagulated), it requires:

• Parallel testing with both APTT and dilute Russell's viper venom time (dRVVT) 1, 3
• Three-step methodology: screening, mixing, and confirmation 1, 2
• Omitting either APTT or dRVVT increases risk of missing diagnosis in up to 55% of triple-positive patients 1, 3

Confirmation Requirements

All positive tests must be repeated at least 12 weeks apart to establish persistence and rule out transient positivity. 1 The same antibodies must be positive on repeat testing to confirm diagnosis 1, 2.

Risk Stratification Based on Results

High-Risk Profile:

• Triple positivity (LA + aCL + aβ2GPI) carries the highest thrombotic risk 1, 3, 2
• Double positivity with concordant isotype (both aCL and aβ2GPI of same isotype) significantly increases diagnostic confidence 1, 3, 2

Moderate-Risk Profile:

• Single LA positivity (though isolated LA without ELISA positivity carries lower risk) 1
• IgG antibodies are clinically more relevant than IgM 1, 2

Lower Clinical Relevance:

• Single IgM positivity without other antibodies requires careful clinical correlation 1, 2, 4
• Low-positive results near cutoff values should be interpreted cautiously due to 10% assay imprecision 1, 2

Practical Algorithm

1. If patient is NOT on anticoagulation: Order comprehensive panel (LA, aCL IgG/IgM, aβ2GPI IgG/IgM) 1

2. If patient IS on anticoagulation:

   • Order aCL IgG/IgM and aβ2GPI IgG/IgM immediately (unaffected by anticoagulation) 1
   • Defer LA testing until anticoagulation can be safely interrupted, OR use DOAC removal procedures, OR use TSVT/ET for VKA patients 1, 2

3. If any test is positive: Repeat the same positive tests after at least 12 weeks 1

4. Interpret results with laboratory-clinician collaboration: Results must be reviewed in clinical context with knowledge of anticoagulation status and potential interferences 1, 2

Important Caveats

• Results around the cutoff value (within 10% margin) may be affected by assay imprecision and should prompt retesting 1, 2
• Acute phase proteins can interfere with LA testing 1, 2
• High variability exists between commercially available assays, so use the local laboratory's established cutoff values 1
• Other antiphospholipid antibody tests (such as antiphosphatidylserine-prothrombin) are not recommended for first-line diagnosis 1