What is the recommended management of antiphospholipid syndrome?

Management of Antiphospholipid Syndrome

For thrombotic APS, lifelong warfarin with target INR 2.0-3.0 is the gold standard treatment; direct oral anticoagulants (especially rivaroxaban) are contraindicated in triple-positive APS due to excess thrombotic events. 1, 2

Risk Stratification

Triple-positive APS (lupus anticoagulant + anticardiolipin + anti-β2 glycoprotein-I antibodies) represents the highest thrombotic risk and requires the most aggressive management. 3, 2

• Lupus anticoagulant positivity alone carries a relative risk of approximately 12 for adverse outcomes 3
• High-titer antibodies (≥40 Units for moderate risk, ≥80 Units for high risk) indicate increased thrombotic risk 3
• Isolated single antibody positivity at low-medium titers represents lower risk 3

Thrombotic APS Management

Venous Thromboembolism

Lifelong warfarin targeting INR 2.0-3.0 is strongly recommended for all patients with venous thrombosis and confirmed APS. 1, 2

• High-intensity warfarin (INR 3.0-4.5) provides no additional benefit over moderate intensity but increases bleeding risk 1
• INR should be monitored at least monthly, with more frequent testing if unstable 3
• Heparin bridging for 5-7 days is recommended when initiating warfarin to prevent transient hypercoagulability from protein C depletion 2

Arterial Thrombosis

Arterial APS carries higher recurrence risk than venous APS and requires either high-intensity warfarin (INR 3.0-4.0) OR moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin 81 mg daily. 3, 4

• The 2021 AHA/ASA guidelines support moderate-intensity warfarin (INR 2.0-3.0) as reasonable for arterial events 1
• Combination therapy with aspirin plus moderate-intensity warfarin is an evidence-based alternative to high-intensity monotherapy 3, 4

Direct Oral Anticoagulants (DOACs)

Rivaroxaban is specifically contraindicated in APS, particularly in triple-positive patients and those with arterial thrombosis, due to excess thrombotic events compared to warfarin. 1, 2

• The 2021 AHA/ASA guidelines give a Class 3 Harm recommendation against rivaroxaban in triple-positive APS 1
• Other DOACs should also be avoided until definitive evidence establishes safety 1, 2, 5
• DOACs might be considered only in highly selected low-risk venous thrombosis patients with warfarin intolerance, but this remains controversial 5, 4

Isolated Antiphospholipid Antibodies (Non-APS)

For patients with isolated positive antiphospholipid antibodies who do not meet full APS criteria, antiplatelet therapy with aspirin alone is recommended over anticoagulation. 1, 2

• The WARSS subgroup analysis showed no differential benefit of warfarin over aspirin in single-positive antibody patients (RR 0.99,95% CI 0.75-1.13) 1
• Aspirin is preferred due to lower bleeding risk compared to warfarin 1

Obstetric APS Management

Confirmed Obstetric APS

Combined therapy with low-dose aspirin (81-100 mg daily) plus prophylactic-dose low molecular weight heparin (LMWH) throughout pregnancy is strongly recommended for all women meeting obstetric APS criteria. 3, 2

• Treatment should start before 16 weeks gestation and continue through delivery 3
• Typical LMWH dosing: enoxaparin 40 mg SC daily or dalteparin 5,000 units SC daily 3
• Hydroxychloroquine may be added as adjunctive therapy, particularly in patients with concurrent SLE 3

Thrombotic APS During Pregnancy

Pregnant women with prior thrombotic APS require therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and for 6-12 weeks postpartum. 3, 2

• Warfarin is contraindicated in the first trimester due to teratogenicity 1
• Anti-Xa monitoring may be needed for therapeutic LMWH dosing 3, 6

Non-Criteria Obstetric APS

For pregnant women with positive antiphospholipid antibodies who do not meet full APS criteria, prophylactic aspirin 81-100 mg daily starting before 16 weeks is conditionally recommended. 3

• Routine prophylactic LMWH is conditionally discouraged in standard-risk patients 3
• Consider adding prophylactic LMWH only in high-risk features: triple-positive antibodies, strongly positive lupus anticoagulant, advanced maternal age, or IVF pregnancy 3

Monitoring During Pregnancy

Monthly clinical assessments, serial fetal ultrasounds with Doppler starting at 16-20 weeks, and laboratory monitoring at least once per trimester are required. 3

• Blood pressure at every visit to detect preeclampsia (2.3-fold increased risk) 3
• Monthly third-trimester Doppler assessments beginning at 28 weeks, increasing to every 1-2 weeks after 32 weeks 3
• Monitor CBC, urinalysis with protein-to-creatinine ratio, serum creatinine, and complement C3/C4 at least once per trimester 3
• Fetal growth restriction occurs 4.7-fold more frequently in high-risk APS 3

Primary Thromboprophylaxis

Low-dose aspirin (75-100 mg daily) is recommended for asymptomatic antiphospholipid antibody-positive patients with high-risk profiles, especially triple-positive or lupus anticoagulant-positive patients. 3, 4

• Testing for APS should be considered in cryptogenic stroke with history of thrombosis or rheumatological disease 1
• In older populations with vascular risk factors, systematic testing for antiphospholipid antibodies is not supported by evidence 1

Anticoagulant-Refractory APS

For patients with recurrent thrombosis despite therapeutic anticoagulation, consider intensifying warfarin to higher INR targets, adding antiplatelet therapy, or adjunctive immunomodulation. 7

• Hydroxychloroquine as adjunctive therapy may be beneficial for refractory APS 3
• Statins may have anti-inflammatory and immunomodulatory benefits 3
• For catastrophic APS, aggressive treatment with combination anticoagulation, glucocorticoids, and plasma exchange is recommended 3

Special Populations

APS with Systemic Lupus Erythematosus

Hydroxychloroquine should be continued throughout pregnancy in patients with both APS and SLE, and anticoagulation is required regardless of current lupus activity level. 3

• For lupus nephritis with antiphospholipid antibodies, antiplatelet agents or anticoagulants are recommended in addition to renin-angiotensin-aldosterone system blockade 1

APS with Sepsis

Continue therapeutic anticoagulation with warfarin (target INR 2.0-3.0) in APS patients with sepsis unless active bleeding or specific contraindication exists. 3

• Sepsis itself is prothrombotic and may synergize with APS thrombotic risk 3
• Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low or active bleeding present 3
• INR monitoring may be unreliable in sepsis due to hepatic dysfunction; monitor for sepsis-induced coagulopathy 3

Critical Monitoring Considerations

Lupus anticoagulant can interfere with INR determination, potentially causing falsely elevated results that do not reflect true anticoagulation intensity. 6, 8

• Consider chromogenic factor X assay or alternative monitoring methods when lupus anticoagulant is strongly positive 6, 8
• Testing for protein C, protein S, or antithrombin should be deferred 4-6 weeks after acute thrombosis as levels may be altered 1

Common Pitfalls

• Never abruptly discontinue warfarin without bridging anticoagulation in thrombotic APS patients 1
• Do not use DOACs in triple-positive APS or arterial thrombosis 1, 2
• Do not rely solely on umbilical-artery Doppler after 34 weeks in pregnancy; incorporate cerebro-placental ratio 3
• Do not add prednisone to standard obstetric APS therapy; controlled trials are lacking and risk profile is unfavorable 3
• Do not withhold aspirin before delivery solely for anesthesia concerns; it does not typically complicate delivery 3