What are the diagnostic criteria and recommended management for antiphospholipid antibody syndrome, including anticoagulation for thrombosis, treatment during pregnancy, and prophylaxis for asymptomatic carriers?

Antiphospholipid Antibody Syndrome

Diagnostic Criteria

Definite APS requires both at least one clinical criterion (thrombosis or pregnancy morbidity) AND at least one laboratory criterion (lupus anticoagulant, anticardiolipin antibodies, or anti-β2-glycoprotein I antibodies), with positive laboratory tests confirmed on two separate occasions at least 12 weeks apart. 1

Clinical Criteria

• Thrombotic events: Any arterial or venous thrombosis at any site, confirmed by imaging or histopathology 1, 2
• Pregnancy morbidity includes:
  • Three or more consecutive spontaneous abortions before 10 weeks of gestation (with maternal anatomic/hormonal abnormalities and paternal/maternal chromosomal causes excluded) 1
  • One or more unexplained fetal deaths at or after 10 weeks of gestation with normal fetal morphology documented by ultrasound or direct examination 1
  • One or more premature births before 34 weeks due to eclampsia, severe preeclampsia, or placental insufficiency (intrauterine growth restriction or fetal distress) 1

Laboratory Criteria

All three antibody types must be tested concurrently—omitting any single test leads to underdiagnosis in up to 55% of triple-positive patients. 3, 2

Required Testing Panel

• Lupus anticoagulant (LAC): Detected using a 3-step methodology (screening, mixing, confirmation) with parallel testing in BOTH activated partial thromboplastin time (APTT) AND dilute Russell's viper venom time (dRVVT) 3, 2
• Anticardiolipin antibodies (aCL): IgG and IgM measured by solid-phase assays (ELISA or automated systems) 3, 1
• Anti-β2-glycoprotein I antibodies (aβ2GPI): IgG and IgM measured by solid-phase assays 3, 1

Positivity Thresholds

• Values must exceed the 99th percentile of healthy controls 3, 1
• The 2023 ACR/EULAR criteria define moderate titer as >40 Units and high titer as >80 Units 1, 2
• Confirmation testing must occur at least 12 weeks (but no later than 5 years) after initial positive result 3, 1

Risk Stratification by Antibody Profile

Triple positivity (LAC + aCL + aβ2GPI) indicates the highest risk for recurrent thrombosis and pregnancy complications—these patients require the most aggressive anticoagulation. 1, 4, 2

• High-risk profiles:

  • Triple-positive (all three antibodies positive) 1, 4, 2
  • Double-positive with concordant IgG isotype (both aCL and aβ2GPI IgG positive) 3, 2
  • Isolated LAC positivity (especially if strongly positive) 4
  • High titer antibodies (>80 Units) 1, 2

• Lower-risk profiles:

  • Isolated aCL or aβ2GPI at low-medium titers (<40 Units) 1, 4
  • Isolated IgM positivity 2, 5

IgG isotype antibodies are clinically more relevant than IgM for thrombotic risk, though IgM may be independently associated with pregnancy morbidity. 2, 5

Testing Limitations and Special Circumstances

• LAC testing during anticoagulation therapy may produce erroneous results 3
• For patients on direct oral anticoagulants (DOACs), pretest DOAC removal procedures can be used 3
• LAC testing during vitamin K antagonist (VKA) therapy should be interpreted with caution; ideally assess 1-2 weeks after VKA discontinuation 3
• aPL levels may fluctuate during pregnancy or around the time of acute thrombosis—results obtained during these periods should be repeated postdelivery or at a distance from the acute event 3

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Management of Thrombotic APS

Venous Thromboembolism

Lifelong warfarin targeting INR 2.0-3.0 is the standard of care for patients with documented venous thromboembolism (deep-vein thrombosis or pulmonary embolism) and persistent antiphospholipid antibodies. 4

• INR should be checked at least monthly, with more frequent testing if unstable 4
• Direct oral anticoagulants (DOACs) should be avoided in all APS patients, especially those with triple-positive or arterial disease 4
• Rivaroxaban is specifically contraindicated (Class III: Harm) in APS patients with thrombosis and triple-positive antibodies due to excess recurrent arterial thrombosis versus warfarin 4

Arterial Thromboembolism

Arterial APS (e.g., stroke) carries higher recurrence risk than venous APS and requires more intensive anticoagulation. 4

Two evidence-based regimens are recommended:

1. High-intensity warfarin with target INR 3.0-4.0, OR
2. Moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin 81 mg daily 4

Asymptomatic Antiphospholipid Antibody Carriers (Primary Prevention)

Aspirin 75-100 mg daily is strongly recommended for patients with high-risk antiphospholipid antibody profiles (triple-positive, double-positive, isolated lupus anticoagulant, or persistently high-titer anticardiolipin) who have no prior thrombosis. 4

• This applies equally to systemic lupus erythematosus (SLE) patients with high-risk aPL profiles 4
• For low-risk aPL profiles (isolated aCL or aβ2GPI at low-to-medium titers), aspirin 75-100 mg daily may be considered after clinician-patient discussion 4
• Aggressive cardiovascular risk-factor modification—including smoking cessation, blood-pressure control, and lipid management—is essential in asymptomatic carriers 4

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Management of Obstetric APS

Confirmed Obstetric APS (Meeting Clinical Criteria)

Combined low-dose aspirin (81-100 mg daily) plus prophylactic-dose low-molecular-weight heparin (LMWH) throughout pregnancy is strongly recommended, achieving approximately 70% live-birth rates. 3, 4

• Aspirin should be initiated before 16 weeks gestation and continued through delivery 3, 4
• Prophylactic LMWH (e.g., enoxaparin 40 mg SC daily or dalteparin 5,000 U SC daily) should be continued for 6-12 weeks postpartum 4
• Hydroxychloroquine 200-400 mg daily may be added to standard therapy for primary APS—small studies suggest fewer pregnancy complications 4

Thrombotic APS in Pregnancy

Therapeutic-dose LMWH (enoxaparin 1 mg/kg SC twice daily or equivalent) together with low-dose aspirin throughout pregnancy and the postpartum period is strongly recommended to prevent recurrent thrombosis. 4

• Anticoagulation must be maintained for at least 6-12 weeks after delivery 4
• Hydroxychloroquine should be continued throughout pregnancy in patients with both APS and SLE 4

Asymptomatic aPL-Positive Pregnant Women (No Clinical APS)

Low-dose aspirin 81-100 mg daily alone is advised, started before 16 weeks and continued through delivery, to modestly reduce obstetric complications. 4

Routine prophylactic LMWH is conditionally recommended against unless the patient exhibits very high-risk features:

• Triple-positive aPL 4
• Strongly positive lupus anticoagulant 4
• Advanced maternal age 4
• IVF conception 4

Assisted Reproductive Technology (ART) in APS

Proceed with ART in women with uncomplicated RMD who are receiving pregnancy-compatible medications, whose disease is stable/quiescent, and who are negative for aPL. 3

For aPL-positive patients undergoing ART:

• Patients with obstetric APS: Treat with prophylactic LMWH/unfractionated heparin during ART procedures 3
• Patients with thrombotic APS: Treat with therapeutic LMWH/unfractionated heparin during ART procedures 3
• Prophylactic LMWH should be started at the beginning of ovarian stimulation, withheld 24-36 hours prior to oocyte retrieval, and resumed following retrieval 4

Pregnancy Monitoring Protocol

Pregnant individuals with APS should undergo monthly clinical assessments, serial fetal ultrasounds with Doppler starting at 16-20 weeks, blood-pressure checks at every visit, and laboratory monitoring of renal function and serological markers at least once per trimester. 4

Maternal Monitoring

• Rheumatology or high-risk obstetric visits at least once per trimester, with more frequent visits (every 2-4 weeks) for triple-positive, LAC-positive, or concurrent SLE patients 4
• Blood-pressure measurement at every prenatal visit—preeclampsia occurs ~2.3-fold more often in APS 4
• Complete blood count, urinalysis with protein-to-creatinine ratio, serum creatinine, and complement C3/C4 levels at least once per trimester 4

Fetal Surveillance

• First-trimester ultrasound (11-14 weeks) to confirm viability and dating 4
• Detailed anatomic survey with Doppler (20-24 weeks) to establish baseline uterine and umbilical-artery flow 4
• Monthly third-trimester Doppler assessments beginning at 28 weeks (umbilical artery, uterine arteries, ductus venosus, middle cerebral artery) 4
• Increase surveillance to every 1-2 weeks after 32 weeks or sooner if abnormalities detected 4
• Monthly fetal biometry in the third trimester to detect IUGR, which occurs ~4.7-fold more frequently in high-risk APS 4

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Catastrophic Antiphospholipid Syndrome (CAPS)

Aggressive treatment with a combination of anticoagulation, glucocorticoids, and plasma exchange is recommended for catastrophic APS. 4

Specific regimen:

• Immediate therapeutic anticoagulation with unfractionated heparin or LMWH 4
• High-dose intravenous glucocorticoids (e.g., methylprednisolone 500-1000 mg daily for 3-5 days, followed by oral prednisone 1 mg/kg/day) 4
• Plasma exchange is associated with improved patient survival and should be initiated promptly 4
• Add intravenous cyclophosphamide (500-1000 mg/m² monthly) if CAPS occurs in the setting of SLE flare 4
• Rituximab has shown potential efficacy in catastrophic APS based on anecdotal reports 4
• Eculizumab (complement C5 inhibitor) has emerging evidence of benefit because complement activation contributes to antibody-mediated tissue injury 4

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Special Considerations

Contraception in aPL-Positive Women

Combined estrogen and progesterone contraceptives are contraindicated in women with positive antiphospholipid antibodies due to increased thrombotic risk. 2

Safe options include:

• Copper IUD 2
• Progestin IUD 2
• Progestin implant 2
• Progestin-only pills 2

APS with Concurrent SLE

• Hydroxychloroquine should be continued throughout pregnancy 4
• Patients with definite APS and SLE require full anticoagulation irrespective of current lupus activity 4
• In primary APS with concurrent SLE, antiplatelet or anticoagulant therapy is advised together with immunosuppression when lupus nephritis is present 4

APS Nephropathy

• Long-term warfarin anticoagulation is reasonable for APS nephropathy, achieving higher complete-response rates (≈60% vs 31% with immunosuppression alone) 4
• Direct oral anticoagulants are not recommended—they are inferior to warfarin in preventing thromboembolic events 4

Refractory APS

• Consider increasing the target INR range for patients who fail standard therapy 4
• Hydroxychloroquine as adjunctive therapy for refractory APS 4
• Rituximab may be considered for patients with recurrent thrombosis despite optimal anticoagulation, although supporting evidence is limited 4

Annual Monitoring

Regular monitoring of LA, aCL, and aβ2GPI is recommended annually to evaluate fluctuation of titers and changes in antibody profile over time. 3, 2

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Common Pitfalls to Avoid

• Do not test for only one or two antibody types—all three (LAC, aCL, aβ2GPI) must be tested concurrently to avoid missing up to 55% of cases 3, 2
• Do not use classification criteria for routine clinical diagnosis—they are more stringent and lead to underdiagnosis 2
• Do not rely on a single positive test—confirmation at ≥12 weeks is mandatory to exclude transient antibodies 3, 1
• Do not use DOACs in triple-positive APS patients—they have higher rates of recurrent thrombosis versus warfarin 4
• Do not discontinue aspirin before delivery solely due to anesthesia concerns—aspirin generally does not interfere with delivery 4
• Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low or there is active bleeding 4
• Do not rely solely on umbilical-artery Doppler after 34 weeks—incorporate cerebro-placental ratio and abdominal-circumference growth velocity 4