What are the diagnostic criteria for Antiphospholipid Syndrome (APS)?

Diagnostic Criteria for Antiphospholipid Syndrome (APS)

APS diagnosis requires BOTH a clinical criterion (thrombosis or pregnancy morbidity) AND persistent laboratory positivity for antiphospholipid antibodies confirmed on two separate occasions at least 12 weeks apart. 1

Laboratory Criteria

You must test for all three antibodies simultaneously, preferably on the same sample 1:

Required Tests

• Lupus anticoagulant (LAC) - detected using functional coagulation assays with a 3-step methodology: screening, mixing, and confirmation 2

  • Must use BOTH activated partial thromboplastin time (APTT) AND dilute Russell's viper venom time (dRVVT) in parallel 2
  • Omitting either APTT or dRVVT increases risk of missing the diagnosis in up to 55% of triple-positive patients 2, 3
  • Report as positive or negative with warnings about potential interferences 2

• Anticardiolipin antibodies (aCL) - IgG and IgM isotypes measured by solid phase assays (ELISA or automated systems) 1

  • Must be present at levels higher than the 99th percentile of normal controls 1
  • Results should be reported with their quantitative level 2

• Anti-β2-glycoprotein I antibodies (aβ2GPI) - IgG and IgM isotypes measured by solid phase assays 1

  • Must be present at levels higher than the 99th percentile of normal controls 1
  • Results should be reported with their quantitative level 2

Confirmation Requirements

• All positive tests must be confirmed after at least 12 weeks to distinguish persistent from transient antibody positivity and avoid over-diagnosis 1, 2
• This 12-week confirmation requirement applies exclusively to positive test results, not negative ones 1
• Two consecutive positive tests are mandatory before making the diagnosis 2, 3

Clinical Criteria (Must Have at Least One)

• Vascular thrombosis: One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ 4, 5
• Pregnancy morbidity: Including unexplained fetal death ≥10 weeks gestation, premature birth <34 weeks due to eclampsia/preeclampsia/placental insufficiency, or three or more unexplained consecutive spontaneous abortions <10 weeks gestation 4, 5

Risk Stratification Based on Antibody Profile

The antibody profile determines thrombotic risk and guides management intensity 2, 3:

• Triple positivity (LAC + aCL + aβ2GPI) - highest thrombotic risk and strongest association with clinical events 1, 3
• Double positivity (aCL + aβ2GPI with concordant isotype) - significantly increases diagnostic confidence 2
• IgG isotype - clinically more relevant than IgM 2, 3
• Medium/high titers (>40 Units) - more clinically significant than low positive results 3
• Single positivity - lower thrombotic risk, particularly if only IgM 2

Critical Testing Considerations and Pitfalls

Anticoagulation Interference

• LAC testing is unreliable during anticoagulation but sometimes clinically necessary 2, 3
• For patients on direct oral anticoagulants (DOACs), use pretest DOAC removal procedures 2, 3
• For patients on vitamin K antagonists (VKAs), use Taipan snake venom time/ecarin time (TSVT/ET), though sensitivity is not 100% 2
• Ideally, assess LAC 1-2 weeks after discontinuing VKA (with or without bridging to LMWH) 2
• Heparin also interferes with LAC testing 1

False Negative Results - When to Retest

Retest negative results if 1:

• Initial testing was performed during anticoagulation therapy
• Testing occurred during acute thrombosis (antibodies may deposit at thrombotic site, lowering serum levels) 1
• Testing was done during pregnancy (Factor VIII increases can mask lupus anticoagulant by shortening APTT) 1
• Strong clinical suspicion persists despite negative standard testing 1

Assay Variability

• Low positive or equivocal results near the cutoff should be repeated, as assay imprecision can reach 10% 1, 2
• Significant inter-assay and inter-laboratory variability exists, particularly for solid-phase assays 1, 6
• Lack of universal calibrators or standards contributes to high variability between different solid-phase assays 6

Emerging Biomarkers (Not Yet Diagnostic Criteria)

• β2GPI domain I antibodies (aD1) - strongly associated with thrombosis in triple-positive patients; currently used for risk confirmation rather than diagnosis 1
• Antiphosphatidylserine/prothrombin antibodies (aPS/PT) - may be considered when standard tests are negative but clinical suspicion remains high 1, 3
• IgA isotypes - significance remains controversial and not included in current diagnostic criteria 1

Updated 2023 ACR/EULAR Criteria

The 2023 ACR/EULAR classification criteria maintain the same laboratory parameters but replaced the 99th percentile cutoff with specific titer thresholds 1:

• Moderate titer: 40 Units
• High titer: 80 Units

Note: Classification criteria (designed for research) are stricter than diagnostic criteria used in clinical practice - inappropriate application of classification criteria may lead to misdiagnosis or underdiagnosis 2