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

Antiphospholipid Syndrome Diagnosis

APS diagnosis requires both clinical manifestations (thrombosis or pregnancy morbidity) AND persistent laboratory positivity for antiphospholipid antibodies confirmed on two separate occasions at least 12 weeks apart. 1, 2

Laboratory Diagnostic Criteria

Required Antibody Testing Panel

Test all three key antiphospholipid antibodies simultaneously: 1, 2

• Lupus anticoagulant (LA) - requires 3-step methodology (screening, mixing, confirmation) using BOTH APTT AND dRVVT in parallel 1, 2
• Anticardiolipin antibodies (aCL) - IgG and IgM isotypes by solid phase assay 1, 2
• Anti-beta2 glycoprotein I antibodies (aβ2GPI) - IgG and IgM isotypes by solid phase assay 1, 2

Critical pitfall: Omitting either APTT or dRVVT in LA testing increases underdiagnosis risk in up to 55% of triple-positive samples. 1, 2 Both tests must be performed in parallel.

Positivity Thresholds

• Values above the 99th percentile of normal controls define positivity 1, 2
• The 2023 ACR/EULAR criteria define moderate titer as ≥40 Units and high titer as ≥80 Units 2, 3
• Medium/high titer antibodies (>40 Units) carry the most clinical significance 1

Confirmation Testing

Repeat all positive tests after exactly 12 weeks (minimum) to confirm persistent positivity and exclude transient antibodies. 4, 1 This confirmation step is mandatory even in triple-positive patients, as it ensures test reliability given poor standardization and potential interferences. 4

Clinical Diagnostic Criteria

Thrombotic Manifestations

One or more episodes of: 3

• Arterial thrombosis (any vascular bed)
• Venous thrombosis (any vascular bed)
• Small vessel thrombosis

Obstetric Manifestations

Any of the following: 2, 3

• Three or more consecutive pregnancy losses before 10 weeks gestation 2
• One or more fetal deaths at or after 10 weeks gestation 2
• Delivery before 34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress 2

Late pregnancy loss shows stronger association with antiphospholipid antibodies than early pregnancy loss. 1

Risk Stratification by Antibody Profile

Highest Risk (Triple Positive)

Positive for all three antibodies (LA + aCL + aβ2GPI) - carries the highest thrombotic risk and worst prognosis. 1, 2, 3 These patients have persistently abnormal profiles on follow-up. 4

High Risk

• Double positivity with concordant IgG isotype (both aCL and aβ2GPI IgG positive) 2
• LA positive alone (strongest predictor for thrombotic events and adverse pregnancy outcomes in obstetric APS and arterial thrombosis) 4
• Medium/high titer antibodies (>40 Units) 1, 2

Lower Risk

• Isolated aCL or aβ2GPI at low-medium titers 3
• IgM isotype alone (IgG isotypes are clinically more relevant) 1, 2

Additional Testing Considerations

When Standard Panel is Negative but Clinical Suspicion Remains High

Consider testing for: 1

• Anti-phosphatidylserine/prothrombin antibodies (aPS/PT) - mainly associated with LAC, may have diagnostic value particularly in obstetric APS 4, 1
• Beta2GPI domain I antibodies (aD1) - strongly associated with thrombosis but currently serve as confirmation of higher thrombotic risk rather than replacement for standard panel 4

Testing Limitations

• Inter-assay and inter-laboratory variability exists; a positive sample in one assay may not test positive in another manufacturer's system 4
• Test results must always be interpreted in clinical context with close laboratory-clinician interaction 4, 2
• LA testing during anticoagulation may be unreliable; for patients on DOACs, use pretest DOAC removal procedures; for patients on warfarin, use Taipan snake venom time/ecarin time 1

Key Differential Diagnoses to Exclude

Systemic Lupus Erythematosus (SLE)

Approximately 30% of SLE patients have antiphospholipid antibodies; APS can be secondary to SLE. 1 Patients with SLE and APS have worse outcomes than primary APS. 1, 2

Thrombotic Thrombocytopenic Purpura (TTP)

Distinguished by severely reduced ADAMTS13 activity (≤10%). 1

Monitoring After Diagnosis

Annual monitoring of LA, aCL, and aβ2GPI is recommended to evaluate titer fluctuation and changes in antibody profile over time. 1, 2 This helps assess ongoing thrombotic risk and guide treatment intensity.