What are the diagnostic criteria for antiphospholipid syndrome (APS)?

Diagnostic Criteria for Antiphospholipid Syndrome (APS)

APS diagnosis requires BOTH clinical manifestations (thrombosis or pregnancy morbidity) AND persistent laboratory evidence of antiphospholipid antibodies confirmed on two separate occasions at least 12 weeks apart. 1, 2

Laboratory Criteria (All Three Tests Required)

Comprehensive testing must include all three antibody types performed concurrently on the same sample: 1, 2

1. Lupus Anticoagulant (LAC)

• Must be detected using two parallel phospholipid-dependent clotting assays: dilute Russell's viper venom time (dRVVT) AND activated partial thromboplastin time (APTT) 1, 3
• Omitting either test misses diagnosis in up to 55% of triple-positive patients 3
• Requires 3-step methodology: screening, mixing, and confirmation 1
• Critical pitfall: NEVER test during anticoagulation therapy - produces unreliable false positive/negative results 1, 2, 3

2. Anticardiolipin Antibodies (aCL)

• IgG and IgM isotypes measured by ELISA or automated solid-phase assays 1
• Must be β2-glycoprotein I-dependent to avoid false positives from infections or drugs 1
• Positive threshold: >99th percentile of normal controls 1

3. Anti-β2-Glycoprotein I Antibodies (aβ2GPI)

• IgG and IgM isotypes measured by ELISA or automated solid-phase assays 1
• Positive threshold: >99th percentile of normal controls 1

Temporal Requirement for Confirmation

All positive antibody tests must be confirmed on repeat testing at least 12 weeks apart to exclude transient antibody positivity unrelated to APS. 1, 4 The same antibodies must remain positive on repeat testing. 1

Clinical Criteria (At Least One Required)

Thrombotic Events

• One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ 2
• Must be confirmed by imaging or histopathology 2

Pregnancy Morbidity

• Unexplained fetal death ≥10 weeks gestation, OR 2
• Premature birth <34 weeks due to eclampsia/preeclampsia/placental insufficiency, OR 2
• ≥3 unexplained consecutive spontaneous abortions <10 weeks gestation 2

Risk Stratification Based on Antibody Profile

Triple-positive patients (LAC + aCL + aβ2GPI of same isotype) carry the highest risk of thrombosis and pregnancy complications, requiring most aggressive management. 1, 2, 3 This profile identifies a single pathogenic class of antibodies directed against domain I of β2-glycoprotein I. 5

Double-positive patients (aCL and aβ2GPI of concordant isotype) have significantly increased diagnostic reliability and elevated risk. 1, 3

Single LAC positivity alone without ELISA positivity actually confers low thrombotic risk. 2, 3

IgG isotype is clinically more relevant than IgM for both aCL and aβ2GPI. 1, 3 Single IgM positivity is regarded as less clinically significant. 1

Critical Testing Pitfalls to Avoid

Anticoagulation Interference

• Do NOT perform LAC testing on anticoagulated patients - this is the most common source of false results 1, 2, 3, 4
• Vitamin K antagonists (VKA), direct oral anticoagulants (DOACs), and heparin all interfere with LAC testing 1, 4
• If testing is unavoidable during anticoagulation, pretest DOAC removal procedures can be used, though interpretation requires extreme caution 1, 3

Pregnancy and Acute Thrombosis

• Factor VIII increases during pregnancy can mask lupus anticoagulant by shortening APTT, producing false negatives 2, 4
• Antibody levels may decrease during acute thrombosis due to antibody deposition at the thrombotic site 2, 4
• Consider retesting if initial results were obtained during these conditions 4

Assay Variability

• High inter-laboratory and inter-assay variability exists for aCL and aβ2GPI testing 1
• Low-positive results near cutoff values should be interpreted cautiously due to 10% assay imprecision 3, 4

Mandatory Laboratory-Clinician Collaboration

Laboratory results must be reviewed through collaboration between a clinical pathologist and a clinician skilled at interpreting the data. 1, 2 Test results must always be related to clinical symptoms and anticoagulation status. 1, 3, 4

LAC should be reported with a final conclusion as positive or negative, including warnings for potential interferences. 1 aCL and aβ2GPI should be reported with their specific levels. 1

Non-Criteria Tests (Not Recommended for Routine Diagnosis)

• Anti-domain I β2GPI antibodies (aD1) remain investigational for risk stratification but are not recommended for first-line diagnosis 1, 3, 4
• Antiphosphatidylserine/prothrombin antibodies (aPS/PT) can be useful when LAC testing is unreliable or uncertain, but should not replace LAC 1, 4
• Other antiphospholipid antibody tests are not recommended 1