Diagnosing Antiphospholipid Syndrome
Diagnose APS when a patient has at least one clinical criterion (thrombosis OR pregnancy morbidity) PLUS at least one laboratory criterion (lupus anticoagulant, anticardiolipin antibodies, or anti-β2-glycoprotein I antibodies) confirmed on two separate occasions at least 12 weeks apart. 1
Laboratory Diagnostic Criteria
The diagnosis requires comprehensive testing of all three antibody types on the same sample: 1
Required Tests
Lupus anticoagulant (LAC) detected in plasma using a combination of two phospholipid-dependent clotting assays (screening, mixing, and confirmation steps), as no single test has sufficient sensitivity and specificity 1
Anticardiolipin antibodies (aCL) IgG/IgM isotype measured by ELISA or automated solid-phase assays, present at levels >99th percentile of normal controls 1
Anti-β2-glycoprotein I antibodies (aβ2GPI) IgG/IgM isotype measured by ELISA or automated solid-phase assays, present at levels >99th percentile of normal controls 1
Confirmation Requirement
All positive tests MUST be repeated and remain positive at least 12 weeks after initial testing to distinguish persistent from transient antibody positivity. 1, 2 This 12-week confirmation requirement applies exclusively to positive results, not negative ones. 2
Clinical Criteria
The patient must have documented evidence of: 1
Thrombosis: One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ, confirmed by imaging or histopathology
Pregnancy morbidity: Including unexplained fetal death ≥10 weeks gestation, premature birth <34 weeks due to eclampsia/preeclampsia/placental insufficiency, or ≥3 unexplained consecutive spontaneous abortions <10 weeks gestation 3
Risk Stratification
Triple-positive patients (LAC + aCL + aβ2GPI of same isotype) have the highest risk of thrombosis and pregnancy complications and require the most aggressive management. 1, 2, 3 When isolated LAC positivity alone is present without ELISA positivity, the thrombotic risk is actually low. 1
Critical Testing Pitfalls to Avoid
Anticoagulation Interference
Do NOT perform LAC testing on patients currently taking anticoagulants (warfarin, DOACs, heparin), as these medications produce unreliable results. 2 If initial testing was performed during anticoagulation, repeat testing off anticoagulation when safe. 2
Pregnancy and Acute Thrombosis Effects
Factor VIII increases during pregnancy can mask lupus anticoagulant by shortening aPTT, producing false negatives. 2 Antibody levels may decrease during acute thrombosis due to antibody deposition at the thrombotic site. 2 If testing was performed during these conditions and results were negative, consider retesting 3 months later if clinical suspicion remains high. 2
Equivocal Results
Low positive or equivocal results near the cutoff value should be repeated, as assay imprecision (up to 10%) can affect classification around cutoff values. 2
Laboratory-Clinician Collaboration
Laboratory results must be reviewed and interpreted through collaboration between a clinical pathologist and a clinician skilled at interpreting the data, as test results must always be related to clinical symptoms. 1, 2 Be aware of significant inter-assay and inter-laboratory variability in these tests. 2
Treatment Implications
Standard APS Management
For patients with documented APS and thrombosis, lifelong anticoagulation with warfarin targeting INR 2.0-3.0 is the standard of care. 4 For patients with documented antiphospholipid antibodies, indefinite treatment is recommended. 4
Critical Contraindication
NEVER use direct oral anticoagulants (DOACs including apixaban, rivaroxaban, dabigatran) in triple-positive APS patients, as they are associated with increased rates of recurrent thrombotic events compared to warfarin. 5, 6, 7 The FDA explicitly warns against DOAC use in triple-positive antiphospholipid syndrome. 6, 7
Catastrophic APS
If catastrophic APS is suspected (multi-organ thrombosis), immediately initiate triple therapy: heparin anticoagulation, high-dose glucocorticoids (methylprednisolone 500-1000 mg IV daily for 3-5 days), and plasma exchange. 5 This combination has been associated with improved survival. 5