What are the diagnostic criteria and management options for Antiphospholipid Syndrome (APS) in patients, particularly women with a history of autoimmune disorders, such as lupus, who present with venous or arterial thrombosis or pregnancy morbidity?

Diagnostic Criteria for Antiphospholipid Syndrome

Definite APS requires both at least one clinical criterion (thrombosis OR pregnancy morbidity) AND at least one laboratory criterion (lupus anticoagulant, anticardiolipin antibodies, or anti-β2-glycoprotein I antibodies), with positive laboratory tests confirmed on two separate occasions at least 12 weeks apart. 1

Clinical Criteria

Vascular Thrombosis

• One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ 2
• Thrombosis must be confirmed by objective validated criteria (imaging studies, Doppler studies, or histopathology) 2
• For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall 2

Pregnancy Morbidity (Any of the following)

• Three or more consecutive spontaneous abortions before 10 weeks of gestation, with maternal anatomic/hormonal abnormalities and paternal/maternal chromosomal causes excluded 1, 3
• One or more unexplained fetal deaths at or after 10 weeks of gestation, with normal fetal morphology documented by ultrasound or direct examination 1, 3
• One or more premature births before 34 weeks due to eclampsia, severe preeclampsia, or recognized features of placental insufficiency (intrauterine growth restriction or fetal distress) 1

Laboratory Criteria (Must be Positive on Two or More Occasions at Least 12 Weeks Apart)

The Three Required Tests

All three tests should be performed on the same sample to fully characterize the antibody profile: 1

1. Lupus Anticoagulant (LAC)

   • Detected in plasma using phospholipid-dependent clotting assays 1
   • Requires a combination of two phospholipid-dependent clotting assays (no single test has sufficient sensitivity and specificity) 1
   • Must follow the multiple-step procedure with screening, mixing, and confirmation steps 1
   • LAC is the strongest predictor of adverse outcomes 3

2. β2-Glycoprotein I-Dependent Anticardiolipin Antibodies (aCL)

   • IgG and/or IgM isotype in serum or plasma 1
   • Present at moderate-to-high titer (>40 units or >99th percentile) 1
   • Measured by solid-phase assays (ELISA or automated systems) 1
   • Must be β2GPI-dependent to avoid detection of non-cofactor-related aCL associated with infections or drugs 1

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

   • IgG and/or IgM isotype in serum or plasma 1
   • Present at moderate-to-high titer (>40 units or >99th percentile) 1
   • Measured by solid-phase assays (ELISA or automated systems) 1

Critical Testing Requirements

• Confirmation testing must occur at least 12 weeks after initial positive result to distinguish persistent from transient antibody positivity 1
• Laboratory results require interpretation through collaboration between a clinical pathologist and a skilled clinician 1
• Comprehensive aPL testing (LAC, aCL, and aβ2GPI IgG and IgM) should be performed, as triple aPL-positive patients are at highest risk of thrombosis or pregnancy morbidity 1

Risk Stratification Based on Antibody Profile

Highest Risk: Triple Positivity

• Triple positivity (LAC + aCL + aβ2GPI of the same isotype) indicates the highest risk of recurrent pregnancy complications and thrombotic events 3, 4
• These patients require the most aggressive management strategies 4

Intermediate Risk: Double Positivity

• Positive for two of the three antibody tests 4
• Particularly high risk when LAC is one of the positive tests 3

Lower Risk: Single Positivity

• Isolated LAC alone carries lower thrombotic risk than when combined with positive ELISA tests 1
• Isolated aCL or aβ2GPI at low-medium titers represents the lowest risk profile 4

Important Caveats

Patients NOT Meeting Full Criteria

• Patients with lower-titer aCL and/or aβ2GPI (<40 units) who do not meet laboratory classification criteria may still have some degree of risk that is difficult to quantify 1
• These patients require individualized risk assessment based on additional clinical factors 1

Testing Limitations

• LAC testing in patients on anticoagulation therapy may cause erroneous results 1
• Isolated LAC positivity without ELISA confirmation carries lower thrombotic risk 1
• Other antiphospholipid antibody tests beyond the three criteria tests are not recommended yet for diagnostic purposes 1

Associated Conditions

• Consider testing for SLE and other autoimmune conditions, given the high rate of co-occurrence with APS 3
• APS can be primary (isolated) or secondary (associated with other autoimmune diseases, especially SLE) 5

When to Test for APS

Testing for aPL should be performed in: 1

• Patients with SLE or SLE-like disease
• Patients with suggestive histories (unexplained thrombosis, recurrent pregnancy loss, thrombocytopenia)
• Patients with suggestive physical findings (livedo reticularis, cardiac valve abnormalities)
• Whether to check these antibodies in other RMD patients with lower likelihood of positive results should be decided through physician-patient discussion 1