What are the diagnostic criteria for Antiphospholipid Antibody (APA) syndrome?

Diagnostic Criteria for Antiphospholipid Antibody Syndrome

The diagnosis of Antiphospholipid Syndrome (APS) requires both clinical criteria (thrombosis or pregnancy morbidity) and laboratory criteria, with positive laboratory tests confirmed after 12 weeks. 1

Laboratory Criteria for APS

The laboratory diagnosis of APS requires at least one of the following criteria:

1. Lupus anticoagulant (LAC) present in plasma, detected according to the Scientific Standardization Subcommittee (SSC) on Lupus Anticoagulant/Phospholipid Antibodies recommendations 1

   • Requires a combination of two phospholipid-dependent clotting assays as no single test has sufficient sensitivity and specificity 1
   • LAC is a well-established thrombotic risk factor, particularly when associated with other antiphospholipid antibodies 1

2. β2GPI-dependent anticardiolipin antibodies (aCL) of IgG/IgM isotype in plasma or serum 1

   • Present at levels higher than the 99th percentile of normal controls 1
   • Measured by solid phase assays (ELISA or automated systems) 1
   • According to the SSC on Lupus Anticoagulant/Phospholipid Antibodies recommendations 1

3. Anti-β2-glycoprotein I antibodies (aβ2GPI) of IgG/IgM isotype in plasma or serum 1

   • Present at levels higher than the 99th percentile 1
   • Measured by solid phase assays (ELISA or automated systems) 1

Important Testing Considerations

• Confirmation testing: Positive laboratory tests must be confirmed after at least 12 weeks to avoid over-diagnosis from transient antibody positivity 1

• Antibody profiles: All three tests should be performed, preferably on the same sample, to characterize the patient's antibody profile 1

  • Triple positivity (LAC + aCL + aβ2GPI of same isotype) shows the strongest association with thrombotic and obstetric APS 1
  • Double-positive patients (mostly LAC negative) generally have lower risk 1
  • Single-positive patients are less likely to develop APS-related events, though isolated LAC can be significant in obstetric APS and arterial thrombosis 1

• Isotype considerations: IgG and IgM isotypes are included in the classification criteria 1

  • The significance of IgA aCL and aβ2GPI remains controversial and requires further research 1

Emerging Biomarkers

• β2GPI domain I antibodies (aD1): A subgroup of IgG aβ2GPI strongly associated with thrombosis 1

  • Mainly present in triple-positive patients 1
  • Currently considered a confirmation of higher thrombotic risk rather than a replacement for aβ2GPI testing 1

• Antibodies to phosphatidylserine/prothrombin (aPS/PT): Show potential diagnostic value 1

  • Mainly associated with LAC 1
  • Additional value in APS diagnosis needs further confirmation 1

Clinical Application

• Test results should always be related to clinical symptoms, requiring interaction between laboratory and clinician 1

• Be aware of inter-assay and inter-laboratory variability - a sample positive in one assay may not test positive in an assay from a different manufacturer 1

• For clinical diagnosis, all test results above the cut-off value (>99th percentile) should be regarded as positive 1

• Triple-positive patients have a persistently abnormal antibody profile and indicate high risk of recurrence of thrombosis or development of a first thrombosis 1

Common Pitfalls and Caveats

• Anticoagulant therapy can interfere with LAC testing, making interpretation difficult 2

• Poor standardization between laboratories can lead to inconsistent results 1, 3

• Classification criteria (used for research) are stricter than diagnostic criteria used in clinical practice 1

• The 2023 ACR/EULAR APS classification criteria maintain the same laboratory parameters but have abandoned the 99th percentile cutoff in favor of moderate (40 Units) and high (80 Units) titer thresholds 1