What is the treatment for antiphospholipid syndrome (APS)?

Treatment of Antiphospholipid Syndrome

For thrombotic APS, adjusted-dose warfarin with target INR 2.5 (range 2.0-3.0) is the first-line treatment and should be continued indefinitely; direct oral anticoagulants must be avoided, especially in triple-positive patients. 1, 2, 3

Thrombotic APS Management

Venous Thrombosis

• Warfarin remains the gold standard anticoagulant with target INR 2.5 (range 2.0-3.0) for all patients with venous thromboembolism in the setting of APS 1, 2, 4, 3
• Initiate warfarin with overlapping parenteral anticoagulation (unfractionated heparin or low molecular weight heparin) until INR is therapeutic for at least 24 hours 1, 3
• Anticoagulation should be continued indefinitely given the persistent thrombotic risk 4, 3

Arterial Thrombosis

• Warfarin with target INR 2.5 (range 2.0-3.0) is recommended, though higher intensity anticoagulation (INR 3.0-4.0) may be considered based on individual thrombotic and bleeding risk 4, 3
• Add low-dose aspirin (75-100 mg daily) to warfarin for all patients with arterial thrombosis 2, 4, 3
• This combination therapy addresses both the thrombotic mechanism and platelet activation seen in arterial events 3

Critical Contraindication: Direct Oral Anticoagulants

• DOACs are explicitly contraindicated in APS, particularly in triple-positive patients (positive lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein-I antibodies) and those with arterial thrombosis 1, 2, 4, 3
• Rivaroxaban specifically shows excess thrombotic events compared to warfarin, with increased risk of arterial thrombosis including stroke 2, 4, 3
• If a patient is already on a DOAC when APS is diagnosed, immediately transition to warfarin therapy 4

Obstetric APS Management

Standard Obstetric APS

• Combined therapy with low-dose aspirin (81-100 mg daily) and prophylactic-dose low molecular weight heparin is strongly recommended throughout pregnancy 1, 2, 4, 3
• Start aspirin before 16 weeks gestation and continue through delivery 4
• Continue prophylactic anticoagulation for 6-12 weeks postpartum due to persistent thrombotic risk 1

Thrombotic APS During Pregnancy

• Use therapeutic-dose low molecular weight heparin plus low-dose aspirin throughout pregnancy and postpartum 1, 4, 3
• Warfarin is absolutely contraindicated during pregnancy due to teratogenicity 3
• Monitor anti-Xa levels for patients on therapeutic heparin to ensure adequate anticoagulation 4

Adjunctive Therapy in Pregnancy

• Addition of hydroxychloroquine to standard heparin and aspirin therapy is conditionally recommended for patients with primary APS 1, 2, 4
• Hydroxychloroquine should be continued during pregnancy as it may reduce pregnancy complications 1, 2
• Despite optimal treatment, pregnancy loss still occurs in approximately 25% of obstetric APS pregnancies 1

Primary Thromboprophylaxis

Asymptomatic High-Risk Patients

• Low-dose aspirin (75-100 mg daily) is recommended for asymptomatic patients with high-risk antiphospholipid antibody profiles 2, 4, 3
• High-risk profiles include: triple-positive antibodies, double-positive antibodies, isolated lupus anticoagulant, or persistently positive anticardiolipin at medium-high titers (≥40 Units) 2, 4

Risk Stratification

• Triple-positive patients (positive for all three antibodies: lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein-I) carry the highest thrombotic risk 2, 4, 3
• Lupus anticoagulant positivity, even in isolation, confers higher risk than isolated anticardiolipin or anti-β2-glycoprotein-I antibodies 4, 3

Refractory APS

Treatment Escalation

• For patients who experience recurrent thrombosis despite therapeutic INR 2.0-3.0, consider increasing the target INR range to 3.0-4.0 4
• Add low-dose aspirin to warfarin if not already prescribed 2, 4
• Consider adding hydroxychloroquine as adjunctive therapy for refractory cases 4, 5
• Statins may provide additional benefit through anti-inflammatory and immunomodulatory properties 2, 5

Catastrophic APS

Aggressive Multi-Modal Therapy

• Catastrophic APS requires immediate aggressive treatment with combination therapy: anticoagulation, high-dose glucocorticoids, and plasma exchange 2, 4, 6
• Intravenous immunoglobulin may be added to the treatment regimen 6
• If catastrophic APS occurs in the setting of systemic lupus erythematosus flare, add intravenous cyclophosphamide (500-1000 mg/m² monthly) 2

Special Populations and Situations

Assisted Reproductive Technology

• Prophylactic anticoagulation with low molecular weight heparin is strongly recommended for patients with obstetric APS undergoing assisted reproductive technology 2, 4
• Therapeutic anticoagulation is required for patients with thrombotic APS undergoing assisted reproductive technology 4
• Start prophylactic low molecular weight heparin at the beginning of ovarian stimulation, withhold 24-36 hours prior to oocyte retrieval, and resume following retrieval 4

Contraception Considerations

• Estrogen-containing contraceptives are absolutely contraindicated in women with positive antiphospholipid antibodies due to significantly increased thrombosis risk 2, 3
• Intrauterine devices and progestin-only pills are recommended contraceptive options 2

APS with Thrombocytopenia

• Thrombocytopenia does not reduce thrombotic risk in APS patients and does not contraindicate anticoagulation unless platelet count is critically low or active bleeding is present 7
• The presence of thrombocytopenia requires individualized assessment of bleeding versus thrombotic risk 7

Monitoring Anticoagulation

Warfarin Monitoring Challenges

• Lupus anticoagulant can interfere with INR measurements, potentially causing falsely elevated results 8
• Consider chromogenic factor X assay for more accurate assessment of anticoagulation intensity in patients with strong lupus anticoagulant positivity 8
• Regular INR monitoring remains essential despite potential interference 8

Low Molecular Weight Heparin Monitoring

• Monitor anti-Xa levels for patients on therapeutic-dose low molecular weight heparin, particularly during pregnancy 4, 8
• Target anti-Xa levels: 0.6-1.0 units/mL for therapeutic dosing, measured 4 hours post-injection 8

Critical Pitfalls to Avoid

• Never use DOACs in triple-positive patients—this is associated with significantly increased thrombotic events including stroke 1, 2, 4, 3
• Do not discontinue anticoagulation prematurely—antiphospholipid antibodies typically persist and thrombotic risk remains elevated indefinitely 4, 3
• Ensure proper overlap of parenteral anticoagulation when initiating warfarin therapy—start warfarin simultaneously with heparin and continue heparin until INR is therapeutic for at least 24 hours 1, 3
• Do not rely on a single positive antibody test—confirmation requires repeat testing at least 12 weeks apart to establish persistence 4, 3
• Avoid estrogen-containing medications in all patients with positive antiphospholipid antibodies 2, 3