Antiphospholipid Antibody Syndrome: Diagnosis and Management
Diagnostic Approach
Diagnosis of APS requires both clinical manifestations (thrombotic events or pregnancy complications) AND persistent laboratory confirmation of antiphospholipid antibodies detected on two separate occasions at least 12 weeks apart. 1
Laboratory Testing
Order all three antibody tests simultaneously on the same sample: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL IgG and IgM), and anti-β2-glycoprotein I antibodies (aβ2GPI IgG and IgM) 2, 1
Positive threshold: Results above the 99th percentile are considered positive, with moderate titers at ≥40 Units and high titers at ≥80 Units per the 2023 ACR/EULAR criteria 2, 1
Confirm persistence: Repeat positive tests after exactly 12 weeks (not sooner) to distinguish persistent from transient antibody positivity 1, 3
Risk stratification by antibody profile 2, 1:
- Triple-positive (LAC + aCL + aβ2GPI of same isotype): Highest thrombotic risk
- Double-positive: Intermediate risk
- Single-positive: Lower risk, though LAC alone remains a strong predictor for obstetric complications and arterial thrombosis
Clinical Criteria
Thrombotic manifestations: Any arterial, venous, or small vessel thrombosis confirmed by imaging or histopathology 1
Obstetric manifestations 1, 3:
- One or more unexplained fetal deaths ≥10 weeks gestation
- One or more premature births <34 weeks due to eclampsia, preeclampsia, or placental insufficiency
- Three or more unexplained consecutive spontaneous abortions <10 weeks gestation
Management of Thrombotic APS
For patients with venous thrombosis and confirmed APS, long-term anticoagulation with warfarin targeting INR 2.0-3.0 (target 2.5) is the gold standard treatment. 1, 4
Anticoagulation Strategy
Warfarin dosing: Target INR 2.5 (range 2.0-3.0) for venous thromboembolism; consider higher intensity (INR 3.0-4.0) for arterial thrombosis or recurrent events despite standard therapy 1, 4
Duration: Indefinite anticoagulation is recommended, particularly for triple-positive patients or those with recurrent thrombosis 4, 5
Avoid DOACs in triple-positive APS: Direct oral anticoagulants show increased rates of recurrent arterial thrombosis, especially stroke, compared to warfarin in triple-positive patients 1
If patient already on DOAC: Transition to warfarin therapy immediately 1
INR Monitoring Challenges
Lupus anticoagulant interferes with INR measurement: The LA can artificially prolong the INR, making it unreliable for monitoring warfarin intensity 6
Use chromogenic Factor X assay when available in LA-positive patients for more accurate assessment of anticoagulation intensity 6
Point-of-care INR devices may be less affected by LA interference, but validation is needed 6
Primary Prevention
Asymptomatic aPL-positive patients: Low-dose aspirin 75-100 mg daily is recommended, especially for high-risk antibody profiles (triple-positive or LAC-positive) 1
Address cardiovascular risk factors aggressively: Statins may provide additional anti-inflammatory benefit 1
Management of Obstetric APS
For confirmed obstetric APS, combined therapy with low-dose aspirin (81-100 mg daily) plus prophylactic-dose LMWH throughout pregnancy is strongly recommended, starting before 16 weeks gestation. 1, 7
Standard Obstetric APS Treatment
Aspirin: 81-100 mg daily, initiated before 16 weeks and continued through delivery 1, 7
Prophylactic LMWH dosing (typical regimens) 1:
- Enoxaparin 40 mg subcutaneous daily, OR
- Dalteparin 5000 units subcutaneous daily
Continue postpartum: Maintain anticoagulation for at least 6 weeks postpartum due to elevated thrombotic risk 1
Thrombotic APS in Pregnancy
For pregnant women with prior thrombotic APS: Use therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum 1, 7
Therapeutic LMWH dosing (weight-based) 1:
- Enoxaparin 1 mg/kg subcutaneous twice daily, OR
- Dalteparin 100 units/kg subcutaneous twice daily
Monitor anti-Xa levels: Target peak anti-Xa 0.6-1.0 units/mL for therapeutic dosing, though routine monitoring is debated 6
Adjunctive Therapy
Add hydroxychloroquine (200-400 mg daily) for patients with primary APS or refractory obstetric APS (pregnancy loss despite standard therapy) 1, 7
Continue hydroxychloroquine in SLE patients: Strongly recommended throughout pregnancy if already taking it 7
Avoid prednisone: Do not add corticosteroids to standard therapy for obstetric APS due to lack of benefit and increased maternal/fetal risks 7
Assisted Reproductive Technology
Start prophylactic LMWH at beginning of ovarian stimulation, withhold 24-36 hours before oocyte retrieval, then resume after retrieval 1
Patients with thrombotic APS undergoing ART: Use therapeutic-dose anticoagulation throughout 1
Management of Catastrophic APS
Catastrophic APS requires immediate aggressive treatment with combination therapy: therapeutic anticoagulation, high-dose intravenous corticosteroids, and plasma exchange or IVIG. 1
Treatment Protocol
Anticoagulation: Therapeutic-dose heparin (UFH or LMWH) initially, transition to warfarin once stabilized 1
High-dose corticosteroids: Methylprednisolone 1000 mg IV daily for 3 days, then taper 1
Plasma exchange: 5-7 sessions over 10-14 days, removing 1-1.5 plasma volumes per session 1
IVIG: 0.4 g/kg/day for 5 days as alternative or addition to plasma exchange 1
Add cyclophosphamide (500-1000 mg/m² monthly) if CAPS occurs with SLE flare 1
Special Consideration: CAPS with Sepsis
Continue therapeutic anticoagulation despite sepsis unless active bleeding or critically low platelets (<20,000/μL) 1
Sepsis is prothrombotic and synergizes with APS thrombotic risk, making anticoagulation even more critical 1
INR monitoring unreliable in sepsis: Use anti-Xa levels or clinical judgment; do not withhold anticoagulation based on elevated INR alone 1
Refractory APS Management
Increase warfarin intensity: Target INR 3.0-4.0 for patients with recurrent thrombosis on standard-intensity therapy 1
Add hydroxychloroquine (200-400 mg daily) to warfarin as adjunctive immunomodulatory therapy 1
Consider LMWH: Switch from warfarin to therapeutic-dose LMWH for truly refractory cases 6
Rituximab or IVIG: Reserve for severe refractory cases unresponsive to standard escalation 8
Monitoring and Follow-up
Regular INR monitoring: Weekly initially, then every 2-4 weeks once stable on warfarin 4
Annual retesting of aPL: Evaluate for fluctuation in titers or change in antibody profile, though therapeutic implications remain unclear 2
Screen for SLE and other autoimmune conditions: High rate of co-occurrence with APS warrants periodic evaluation 3
Pregnancy monitoring: Increased surveillance with serial ultrasounds, fetal monitoring, and assessment for preeclampsia 9
Critical Pitfalls to Avoid
Do not use DOACs in triple-positive APS: This is associated with significantly increased arterial thrombotic events 1
Do not stop anticoagulation for minor procedures: Coordinate with hematology; even brief interruptions can trigger catastrophic APS 10
Do not rely on INR alone in LA-positive patients: Consider chromogenic Factor X assay for accurate warfarin monitoring 6
Do not use hydroxychloroquine as monotherapy: It must be added to anticoagulation, never used alone 7
Do not test aPL during acute thrombosis: Transient elevations are common; wait until clinical stability, then confirm persistence at 12 weeks 2