What is the treatment for Antiphospholipid Syndrome (APS)?

Treatment of Antiphospholipid Syndrome (APS)

For thrombotic APS, long-term warfarin with target INR 2.0-3.0 is the gold standard treatment; direct oral anticoagulants (DOACs) should be avoided, especially in triple-positive patients or those with arterial thrombosis. 1, 2, 3, 4

Thrombotic APS Management

Venous Thrombosis

• Warfarin remains the cornerstone therapy with target INR 2.5 (range 2.0-3.0) for indefinite duration 1, 2, 3, 4
• Initiate warfarin with overlapping parenteral anticoagulation (unfractionated heparin or LMWH) until INR is therapeutic for at least 24 hours 3, 4
• DOACs are explicitly contraindicated in APS, particularly in triple-positive patients (positive for lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein-I antibodies), due to significantly increased rates of recurrent thrombotic events compared to warfarin 1, 2, 3
• If a patient is already on a DOAC, transition immediately to warfarin therapy 3

Arterial Thrombosis

• Warfarin with target INR 2.5 (range 2.0-3.0) plus low-dose aspirin (75-100 mg daily) is recommended 2, 3
• Some guidelines suggest considering higher intensity anticoagulation (INR 3.0-4.0) for arterial events, though this must be balanced against bleeding risk 3
• Never use DOACs for arterial thrombosis in APS - this is associated with particularly high rates of recurrent stroke 2, 3

Risk Stratification Considerations

The antibody profile determines thrombotic risk and influences management intensity:

• Triple-positive patients (all three antibodies positive) have the highest thrombotic risk and require the most stringent avoidance of DOACs 2, 3
• Lupus anticoagulant positivity, even in isolation, confers higher risk than other antibodies alone 3
• Double-positive or persistently high-titer antibodies also indicate elevated risk 2, 5

Obstetric APS Management

Standard Obstetric APS

• Combined therapy with low-dose aspirin (81-100 mg daily) and prophylactic-dose LMWH throughout pregnancy and postpartum is strongly recommended 2, 3, 5
• Start aspirin before 16 weeks gestation and continue through delivery 2
• Warfarin is absolutely contraindicated during pregnancy due to teratogenicity 3

Thrombotic APS During Pregnancy

• Therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum 2, 3
• Monitor anti-Xa levels to ensure therapeutic anticoagulation 2

Assisted Reproductive Technology (ART)

• For obstetric APS patients undergoing ART: prophylactic LMWH starting at ovarian stimulation, withheld 24-36 hours before oocyte retrieval, then resumed 2
• For thrombotic APS patients undergoing ART: therapeutic-dose anticoagulation throughout 2

Primary Thromboprophylaxis (Asymptomatic Carriers)

High-Risk Antibody Profiles

• Low-dose aspirin (75-100 mg daily) for asymptomatic patients with high-risk profiles including: 2, 3, 5
  • Triple-positive antibodies
  • Double-positive antibodies with lupus anticoagulant
  • Persistently positive anticardiolipin at medium-high titers (≥40 Units)
  • Isolated lupus anticoagulant

Pregnant Women Without Prior APS

• Prophylactic aspirin (81-100 mg daily) starting before 16 weeks for antiphospholipid antibody-positive pregnant women who don't meet full APS criteria 2

Adjunctive Therapies

Hydroxychloroquine

• Addition of hydroxychloroquine to standard anticoagulation is conditionally recommended for patients with primary APS 2, 3
• Recent studies suggest it may decrease thrombotic complications and pregnancy morbidity 2
• Should be continued during pregnancy 2, 5
• Consider for anticoagulant-refractory APS 2

Statins

• May have a role due to anti-inflammatory and immunomodulatory properties 2
• Consider as adjunctive therapy in high-risk or refractory cases 6

Anticoagulant-Refractory APS

When thrombosis recurs despite therapeutic anticoagulation:

• First, verify true therapeutic anticoagulation - lupus anticoagulant can interfere with INR monitoring, making results unreliable 7
• Increase target INR range to 3.0-4.0 if recurrent thrombosis occurs on standard-intensity warfarin 2, 8
• Add low-dose aspirin (75-100 mg daily) to warfarin if not already prescribed 3, 8
• Consider switching to therapeutic-dose LMWH with anti-Xa monitoring 8
• Add hydroxychloroquine as adjunctive immunomodulatory therapy 2, 8
• Consider statins for additional anti-inflammatory effects 8

Catastrophic APS (CAPS)

This life-threatening variant requires aggressive multimodal therapy:

• Combination of anticoagulation, high-dose glucocorticoids, and plasma exchange 2, 5
• If occurring in the setting of SLE flare, add intravenous cyclophosphamide (500-1000 mg/m² monthly) 2
• Consider IVIG as additional therapy 2

Special Populations and Situations

APS with Systemic Lupus Erythematosus (SLE)

• Manage thrombotic risk with same anticoagulation strategies as primary APS 3
• Continue hydroxychloroquine - it reduces both lupus activity and thrombotic risk 1, 2
• For lupus nephritis with positive antiphospholipid antibodies, consider antiplatelet/anticoagulant therapy in combination with immunosuppression 1

APS with Thrombocytopenia

• Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low (<50,000/μL) or active bleeding is present 2
• Balance thrombotic risk (which remains high) against bleeding risk 8

Contraception in Women with APS

• Estrogen-containing contraceptives are absolutely contraindicated due to markedly increased thrombosis risk 3, 5
• Recommend intrauterine devices or progestin-only pills as safe alternatives 5

Critical Pitfalls to Avoid

• Never use rivaroxaban or other DOACs in triple-positive APS - this is associated with excess arterial thrombotic events, particularly stroke 1, 2, 3
• Do not discontinue anticoagulation prematurely - antibodies typically persist lifelong and thrombotic risk remains elevated; indefinite anticoagulation is usually required 3, 4
• Do not rely on single positive antibody test - confirmation requires repeat testing at least 12 weeks apart to establish persistence 2, 3
• Ensure proper overlap of parenteral anticoagulation when initiating warfarin - start heparin or LMWH simultaneously and continue until INR is therapeutic for at least 24 hours 3, 4
• Be aware that lupus anticoagulant interferes with INR monitoring - results may not reflect true anticoagulation intensity, potentially leading to under- or over-anticoagulation 7
• Do not use warfarin during pregnancy - switch to LMWH before conception or immediately upon pregnancy recognition 3