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

Diagnostic Criteria for Antiphospholipid Syndrome (APS)

The diagnosis of Antiphospholipid Syndrome (APS) requires at least one clinical criterion (thrombosis or pregnancy morbidity) AND one laboratory criterion (lupus anticoagulant, anticardiolipin antibodies, or anti-β2-glycoprotein I antibodies), with positive laboratory tests confirmed after at least 12 weeks. 1

Clinical Criteria

• Vascular Thrombosis:

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

• Pregnancy Morbidity (any of the following):

  • One or more unexplained deaths of morphologically normal fetuses at or beyond 10 weeks of gestation
  • One or more premature births of morphologically normal neonates before 34 weeks due to:
    • Severe preeclampsia
    • Eclampsia
    • Placental insufficiency
  • Three or more unexplained consecutive spontaneous abortions before 10 weeks of gestation

Laboratory Criteria

• Lupus Anticoagulant (LA):

  • Must be detected according to ISTH guidelines using two phospholipid-dependent coagulation tests 2
  • Recommended tests include dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (APTT)
  • Must be positive on two or more occasions at least 12 weeks apart

• Anticardiolipin Antibodies (aCL):

  • IgG and/or IgM isotype in medium or high titer (>40 Units or >99th percentile)
  • Must be detected by standardized ELISA
  • Must be positive on two or more occasions at least 12 weeks apart

• Anti-β2 Glycoprotein I Antibodies (aβ2GPI):

  • IgG and/or IgM isotype in titer >99th percentile
  • Must be detected by standardized ELISA
  • Must be positive on two or more occasions at least 12 weeks apart

Risk Stratification

• Triple Positivity (LA + aCL + aβ2GPI) identifies patients with the highest thrombotic risk 1
• Single LA Positivity carries a lower thrombotic risk than triple positivity 2
• Antibody Titer Levels:
  • Moderate titer: >40 Units
  • High titer: >80 Units 2

Important Diagnostic Considerations

1. Classification vs. Clinical Diagnosis:

   • Classification criteria (as outlined above) are strict and designed for research studies
   • Clinical diagnosis may be broader and more flexible for patient care 2
   • Inappropriate application of classification criteria may lead to underdiagnosis

2. Laboratory Testing Challenges:

   • LA testing should be avoided during anticoagulant therapy, especially vitamin K antagonists 2
   • Two parallel tests for LA are required (dRVVT and APTT) as using only one increases risk of underdiagnosis by up to 31% in APS patients 2
   • Significant variability exists between laboratories and assays

3. Timing of Testing:

   • Initial positive tests should be confirmed after at least 12 weeks
   • Testing too close to a thrombotic event or during pregnancy may affect results
   • Transient positivity can occur during infections or with certain medications

4. Non-criteria Antibodies:

   • Anti-domain I β2-glycoprotein I antibodies (aD1) are strongly associated with thrombosis 1
   • Antiphosphatidylserine/prothrombin antibodies (aPS/PT) show promise but require further validation 1
   • IgA isotypes of aCL and aβ2GPI may be relevant in some patients but are not part of formal criteria

Pitfalls to Avoid

• Relying on a single positive test without confirmation after 12 weeks
• Testing during acute thrombosis or active infection, which can cause transient positivity
• Failing to use two different tests for LA detection
• Diagnosing APS based on laboratory criteria alone without clinical manifestations
• Using non-standardized laboratory methods for antibody detection
• Overlooking "seronegative APS" in patients with typical clinical features but negative standard tests 3

By systematically evaluating both clinical and laboratory criteria, clinicians can accurately diagnose APS and implement appropriate management strategies to reduce morbidity and mortality associated with this syndrome.