What are the initial steps in the workup and management of a patient suspected of having antiphospholipid syndrome (APS)?

Antiphospholipid Syndrome Workup

Test for all three mandatory antiphospholipid antibodies simultaneously: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM, then repeat the same positive tests at least 12 weeks later to confirm persistent positivity. 1, 2, 3

Initial Laboratory Testing

Core Antibody Panel (Mandatory)

• Lupus anticoagulant (LA) requires a rigorous 3-step methodology: screening test, mixing study, and confirmatory test 1, 2, 3

• Use BOTH dRVVT (dilute Russell's viper venom time) AND APTT (activated partial thromboplastin time) in parallel for LA detection—omitting either test increases underdiagnosis risk by up to 55% in triple-positive patients 1, 2, 3

• Anticardiolipin antibodies (aCL) IgG and IgM by ELISA or validated solid-phase assay 2, 3

• Anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG and IgM by ELISA or validated solid-phase assay 2, 3

• Report all results quantitatively with titers; positivity is defined as values above the 99th percentile of normal controls 2, 3

• The 2023 ACR/EULAR criteria define moderate titer as ≥40 Units and high titer as ≥80 Units 1, 3

Confirmation Testing

• Repeat the SAME positive tests after exactly 12 weeks (minimum) to confirm persistent positivity and exclude transient antibodies 1, 2, 3

• This repeat testing ensures reliability given poor standardization and potential interferences 1

Risk Stratification Based on Antibody Profile

Highest Risk: Triple Positivity

• Patients positive for LA + aCL + aβ2GPI carry the highest thrombotic risk and require most aggressive management 2, 3

High Risk Features

• Medium to high antibody titers (>40 Units) 2, 3
• IgG isotype antibodies (more clinically relevant than IgM) 2, 3
• Double positivity with concordant isotype (both aCL and aβ2GPI of same isotype, particularly IgG) 3

Lower Risk

• Single antibody positivity, particularly isolated LA 1

Additional Testing in Select Cases

When Standard Panel is Negative but Clinical Suspicion Remains High

• Antiphosphatidylserine/prothrombin (aPS/PT) antibodies may be considered when LA, aCL, and aβ2GPI are negative but clinical suspicion is strong 2, 4

• aPS/PT antibodies have shown favorable diagnostic value and are particularly associated with late pregnancy loss 1, 4

• Anti-domain I beta2 glycoprotein I antibodies (aD1) can confirm higher thrombotic risk in triple-positive patients but have no added diagnostic value to the standard panel 1

Critical Timing Considerations

Testing During Anticoagulation

• LA testing is unreliable during anticoagulation therapy 2, 5

• For patients on DOACs: use pretest DOAC removal procedures 2

• For patients on VKAs: consider Taipan snake venom time/ecarin time as alternative 2

• Interpret LA as absent with a comment on repeat testing and potential false negatives when tested during VKA therapy or coagulation factor deficiency 1

Optimal Testing Window

• Test before initiating anticoagulation whenever possible 5, 6

• If patient already anticoagulated (common after thrombotic event), document this limitation and plan repeat testing off anticoagulation when safe 5

Clinical Context Assessment

Thrombotic Manifestations to Document

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) 6, 7
• Arterial thrombosis (stroke, myocardial infarction, peripheral arterial thrombosis) 6, 7
• Microvascular thrombosis 6

Obstetric Manifestations to Document

• Three or more consecutive pregnancy losses before 10 weeks gestation 3
• One or more fetal losses at or after 10 weeks gestation 3
• Premature delivery before 34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress 3

Associated Conditions to Evaluate

• Screen for systemic lupus erythematosus (SLE)—approximately 30% of SLE patients have antiphospholipid antibodies 2
• Check complement levels (C3, C4) and inflammatory markers (CRP) 4
• Consider autoimmune panel if lupus-like features present 4

Common Pitfalls to Avoid

• Never dismiss patients based on negative standard aPL testing alone when clinical suspicion is high—consider aPS/PT antibodies 4

• Never use classification criteria as diagnostic criteria—clinical diagnosis should be broader to optimize patient care 4

• Never order only LA or only solid-phase assays—the complete panel is mandatory 1, 2, 3

• Never accept single positive test as diagnostic—persistence at 12+ weeks is required 1, 2, 3

• Never use APTT alone to screen for LA—it is prolonged in only 40-50% of patients with lupus anticoagulant 7

Ongoing Monitoring After Diagnosis

• Annual monitoring of LA, aCL, and aβ2GPI to evaluate titer fluctuation and antibody profile changes over time 1, 2, 3

• Serial monitoring every 3-6 months including repeat complete aPL panel, CRP, and complement levels to track disease activity 4

• Close laboratory-clinician interaction is essential for proper interpretation of results in clinical context 1, 3