For what clinical indications are lupus anticoagulant, anticardiolipin antibody, and anti‑β2‑glycoprotein I assays ordered?

Clinical Indications for Antiphospholipid Antibody Testing

Lupus anticoagulant, anticardiolipin antibody, and anti-β2 glycoprotein I levels are used to diagnose antiphospholipid syndrome (APS) in patients presenting with unexplained thrombosis (arterial, venous, or small vessel) or specific pregnancy complications, and all three tests must be performed together on the same sample. 1, 2, 3

Core Clinical Scenarios Requiring Testing

Thrombotic Events

• Unexplained arterial thrombosis at any site (stroke, myocardial infarction, peripheral arterial occlusion) warrants complete antiphospholipid antibody testing 3, 4
• Unexplained venous thromboembolism (deep vein thrombosis, pulmonary embolism) at any site, particularly in patients under 50 years old or with recurrent events 3, 4
• Small vessel thrombosis in any tissue or organ confirmed by imaging or histopathology 4
• Unusual site thrombosis such as cerebral venous sinus thrombosis, mesenteric vein thrombosis, or hepatic vein thrombosis (Budd-Chiari syndrome) 2

Pregnancy-Related Indications

• Three or more consecutive spontaneous pregnancy losses before 10 weeks of gestation with no other identifiable cause 2, 3
• One or more unexplained fetal deaths at or after 10 weeks of gestation 2, 3
• Premature delivery before 34 weeks due to severe preeclampsia, eclampsia, or placental insufficiency 3, 4

Additional Clinical Contexts

• Patients with systemic lupus erythematosus (SLE) being evaluated for thrombotic risk or pregnancy planning 5, 6
• Unexplained prolonged activated partial thromboplastin time (aPTT) discovered incidentally 7, 8

The Complete Testing Panel

All three antibody types must be tested simultaneously because each detects different antibody populations, and omitting any test leads to substantial underdiagnosis 1, 2, 3:

Lupus Anticoagulant (LA)

• Requires two parallel functional clotting assays: dilute Russell's viper venom time (dRVVT) AND lupus-sensitive activated partial thromboplastin time (APTT) 2, 3, 4
• Omitting either dRVVT or APTT misses the diagnosis in up to 55% of triple-positive patients and 31% of all APS patients 2, 3
• Critical pitfall: Never test for LA while the patient is on anticoagulation therapy (warfarin, heparin, or direct oral anticoagulants), as this produces unreliable false-positive or false-negative results 2, 4

Anticardiolipin Antibodies (aCL)

• Measured by ELISA or validated solid-phase assays for both IgG and IgM isotypes 1, 3, 4
• Positive when levels exceed the 99th percentile of normal controls 1, 3, 4
• The 2023 ACR/EULAR criteria define moderate titer as >40 Units and high titer as >80 Units 1, 3

Anti-β2 Glycoprotein I Antibodies (aβ2GPI)

• Measured by ELISA or validated solid-phase assays for both IgG and IgM isotypes 1, 3, 4
• Same positivity thresholds as aCL: >99th percentile, with moderate >40 Units and high >80 Units 1, 3

Confirmation Testing Requirements

Any positive result must be repeated at least 12 weeks later (but no later than 5 years) to confirm persistence and exclude transient antibody positivity from infections or other causes 2, 3, 4. This mandatory repeat testing applies even to triple-positive patients who typically maintain persistent abnormalities 3.

Risk Stratification Based on Results

The antibody profile directly determines thrombotic risk and guides management intensity 1, 2:

• Triple-positive (LA + aCL + aβ2GPI, all positive): Highest risk for thrombosis and pregnancy complications, requires most aggressive anticoagulation 1, 2, 3, 4
• Double-positive (aCL and aβ2GPI of concordant isotype, particularly IgG): Significantly elevated risk and high diagnostic reliability 1, 2, 3
• Single LA-positive: Moderate risk, substantially lower than triple positivity 2, 3
• IgG isotype: Clinically more relevant than IgM for both aCL and aβ2GPI 1, 2, 3
• Isolated IgM positivity: Considered less clinically significant 1, 3

Critical Distinction: Classification vs. Clinical Diagnosis

The 2023 ACR/EULAR classification criteria are designed for research studies and are more stringent than clinical diagnostic criteria 1, 2, 3. Using classification criteria for routine clinical diagnosis leads to underdiagnosis and missed cases 1, 2. In daily practice, the diagnostic approach should be broader to identify every patient who needs treatment, even if they don't meet strict classification criteria 1, 2.

Common Pitfalls to Avoid

• Never test LA during anticoagulation: This is the most common source of false results 2, 4
• Factor VIII elevation during pregnancy can mask lupus anticoagulant by shortening aPTT, producing false negatives 4
• Antibody levels may decrease during acute thrombosis due to antibody deposition at the thrombotic site 4
• Low-positive results near cutoff values should be interpreted cautiously due to 10% assay imprecision and high inter-laboratory variability 2, 7, 8

Interpretation and Collaboration

Laboratory results must be interpreted in clinical context with knowledge of the patient's anticoagulation status, and close collaboration between the laboratory and clinician is essential for proper interpretation 2, 3, 4. Test results must always be correlated with clinical symptoms 3, 4.