What is the recommended treatment for antiphospholipid syndrome (APS)?

Treatment for Antiphospholipid Syndrome

For thrombotic APS, lifelong 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, due to increased risk of recurrent arterial thrombosis. 1, 2

Risk Stratification

Before initiating treatment, determine the patient's antibody profile and clinical phenotype:

• Triple-positive patients (positive for lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies) carry the highest thrombotic risk and require the most aggressive management 2, 3
• Moderate-to-high antibody titers (≥40 Units or ≥99th percentile) indicate significant risk 2
• Lupus anticoagulant positivity alone confers substantial thrombotic risk even without other antibodies 2
• Laboratory confirmation requires persistent positivity on two occasions at least 12 weeks apart 2

Treatment by Clinical Phenotype

Thrombotic APS (History of Venous Thrombosis)

Lifelong warfarin with target INR 2.0-3.0 is strongly recommended. 1, 2, 4

• This applies to all patients with documented venous thromboembolism (DVT or PE) and persistent antiphospholipid antibodies 4, 5
• The American College of Chest Physicians endorses this as Grade 1B evidence 2
• Never use DOACs in triple-positive APS patients—rivaroxaban specifically increases thrombotic events compared to warfarin 1
• If a patient is already on a DOAC, transition immediately to warfarin 2
• DOACs may be considered only in highly selected low-risk venous thrombosis patients with single antibody positivity who cannot tolerate warfarin, but this remains controversial 5

Thrombotic APS (History of Arterial Thrombosis)

Two evidence-based options exist:

1. High-intensity warfarin (target INR 3.0-4.0) 2, 5
2. Moderate-intensity warfarin (INR 2.0-3.0) plus low-dose aspirin 81-100 mg daily 2, 3

• Arterial events (especially stroke) carry higher recurrence risk than venous events 1
• The choice between these regimens depends on bleeding risk assessment 5
• Avoid DOACs entirely for arterial thrombotic APS 1, 2

Asymptomatic Antiphospholipid Antibody-Positive Patients (Primary Prevention)

Low-dose aspirin 75-100 mg daily is recommended for high-risk antibody profiles. 2

High-risk features warranting aspirin include:

• Triple-positive antibody profile 2
• Strongly positive lupus anticoagulant 2
• Moderate-to-high antibody titers (≥40 Units) 2
• Concomitant systemic lupus erythematosus 1
• Multiple traditional cardiovascular risk factors 5

Do not use prophylactic anticoagulation in asymptomatic patients without additional risk factors 2

Obstetric APS (Pregnancy Morbidity Without Thrombosis)

Combined low-dose aspirin (81-100 mg daily) plus prophylactic-dose low molecular weight heparin (LMWH) throughout pregnancy is strongly recommended. 2, 6

Specific dosing:

• Enoxaparin 40 mg subcutaneously once daily OR dalteparin 5,000 Units subcutaneously once daily 6
• Start aspirin before 16 weeks gestation and continue through delivery 2, 6
• Continue LMWH for 6-12 weeks postpartum 6
• This regimen achieves approximately 70% live-birth rates 6

Adding hydroxychloroquine 200-400 mg daily to standard therapy is conditionally recommended for primary APS, as emerging data suggest reduced pregnancy complications 2, 6

Thrombotic APS During Pregnancy

Therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and 6-12 weeks postpartum is required. 2, 6

• Enoxaparin 1 mg/kg subcutaneously twice daily OR dalteparin 100 Units/kg subcutaneously twice daily 6
• This is non-negotiable for any patient with prior thrombotic events 6
• Never use warfarin during pregnancy due to teratogenicity 6, 7
• Warfarin may be resumed postpartum and is compatible with breastfeeding 6

Peripartum Management

• Stop LMWH 24 hours before scheduled cesarean section or neuraxial anesthesia 6, 7
• Continue aspirin through delivery—it does not interfere with anesthesia 6, 7
• Resume therapeutic LMWH 6-12 hours after vaginal delivery or 12-24 hours after cesarean section once hemostasis is confirmed 6, 7
• Apply intermittent pneumatic compression devices intraoperatively 7

Catastrophic APS

Aggressive triple therapy with anticoagulation, high-dose glucocorticoids, and plasma exchange is recommended. 2

• Add intravenous cyclophosphamide 500-1000 mg/m² monthly if catastrophic APS occurs with SLE flare 2
• Consider eculizumab (complement inhibitor) or rituximab in refractory cases 8, 9
• This is a medical emergency requiring intensive care 2

Adjunctive Therapies

Hydroxychloroquine

Conditionally recommended for primary APS at 200-400 mg daily. 2, 6

• May reduce thrombotic complications and improve pregnancy outcomes 2, 6
• Should be continued throughout pregnancy in patients already taking it 1
• Do not use in asymptomatic antibody-positive patients without other indications 2

Therapies to Avoid

• Prednisone should not be added to standard APS therapy—no controlled trials demonstrate benefit and the risk profile is unfavorable 2, 6
• Intravenous immunoglobulin (IVIG) has no demonstrated benefit in refractory obstetric APS 2
• High-dose LMWH escalation beyond standard therapeutic dosing is not supported by evidence 2

Monitoring Requirements

For Warfarin Therapy

• Target INR 2.0-3.0 for venous thrombosis 1, 2, 4
• Target INR 3.0-4.0 for arterial thrombosis (if high-intensity strategy chosen) 2, 4
• Monthly INR monitoring minimum; more frequent if unstable 4

For LMWH in Pregnancy

• Anti-Xa monitoring is not routinely required for prophylactic dosing 6
• Consider anti-Xa levels for therapeutic dosing or extreme body weight 6
• Monthly complete blood count, urinalysis with protein-to-creatinine ratio, serum creatinine, and complement C3/C4 2

Pregnancy-Specific Surveillance

• Monthly clinical assessments with rheumatology or high-risk obstetrics 2
• Serial fetal ultrasounds with Doppler starting at 16-20 weeks, then monthly in third trimester 2
• Blood pressure at every visit—preeclampsia occurs 2.3-fold more often in APS 2
• Intensify to every 1-2 weeks after 32 weeks or sooner if abnormalities detected 2

Critical Pitfalls to Avoid

• Never use rivaroxaban in APS—it is specifically associated with excess thrombotic events versus warfarin 1
• Do not discontinue anticoagulation in sepsis unless active bleeding or critically low platelets—sepsis is prothrombotic and synergizes with APS thrombotic risk 2
• Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low (<20,000-30,000/μL) or active bleeding is present 2, 10
• Do not extend LMWH discontinuation beyond 24 hours before cesarean section—this significantly increases thrombotic risk 7
• Do not assume normal complement levels exclude SLE flare in pregnant patients—look for declining trends even within normal range 2
• Do not use vitamin K antagonists after 36 weeks gestation due to risk of fetal intracranial hemorrhage 6

Special Populations

APS with Systemic Lupus Erythematosus

• Hydroxychloroquine should be continued throughout pregnancy 1
• Antiplatelet or anticoagulant therapy is recommended in combination with immunosuppression if lupus nephritis is present 1
• Patients with definite APS and SLE require full anticoagulation regardless of lupus activity 1

Renal Transplant Candidates with APS

• Transplantation should be performed when clinical and serological lupus activity is absent or low for at least 3-6 months 1
• Patients with moderate-to-high antiphospholipid antibody titers should receive perioperative anticoagulation 1

Assisted Reproductive Technology (ART)

• Defer ART if APS disease is moderately or severely active 2
• For obstetric APS: prophylactic LMWH starting at ovarian stimulation, held 24-36 hours before oocyte retrieval, resumed after retrieval 2
• For thrombotic APS: therapeutic anticoagulation throughout ART 2