What is the recommended treatment for antiphospholipid syndrome (APS), including anticoagulation strategy, management during pregnancy, and therapy for catastrophic APS?

Treatment of Antiphospholipid Syndrome

For thrombotic APS, lifelong warfarin with target INR 2.0-3.0 is the gold standard for venous events, while arterial events require either high-intensity warfarin (INR 3.0-4.0) or moderate-intensity warfarin plus low-dose aspirin; direct oral anticoagulants should be avoided, especially in triple-positive patients. 1, 2, 3

Anticoagulation Strategy for Thrombotic APS

Venous Thromboembolism

• Warfarin with target INR 2.5 (range 2.0-3.0) is the cornerstone of treatment for patients with venous thrombosis (deep vein thrombosis or pulmonary embolism). 1, 2, 3
• Anticoagulation must be lifelong due to high recurrence rates without vitamin K antagonist therapy. 1, 2
• INR monitoring should occur at least monthly, with more frequent testing if results are unstable. 3

Arterial Thromboembolism

• Two evidence-based regimens exist for arterial events (stroke, myocardial infarction): 2, 3
  • High-intensity warfarin targeting INR 3.0-4.0, or
  • Moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin 75-100 mg daily
• Arterial APS carries higher recurrence risk than venous APS, justifying more aggressive therapy. 2, 3

Critical Anticoagulant Selection

• Direct oral anticoagulants (DOACs) are explicitly contraindicated in APS, particularly in triple-positive patients, due to increased rates of recurrent arterial thrombosis and stroke compared with warfarin. 1, 2, 3
• Rivaroxaban specifically is associated with excess thrombotic events versus warfarin. 2, 3
• If a patient is already on a DOAC, transition immediately to warfarin therapy. 3

Adjunctive Therapy

• Low-dose aspirin (75-100 mg daily) should be added for patients with high-risk antibody profiles (triple-positive, double-positive, or isolated lupus anticoagulant at high titers), even in asymptomatic patients for primary prevention. 1, 2
• Hydroxychloroquine is conditionally recommended as adjunctive therapy for patients with primary APS and should be continued in patients with concurrent systemic lupus erythematosus. 2, 3

Management During Pregnancy

Obstetric APS (Recurrent Pregnancy Loss)

• Combined low-dose aspirin (81-100 mg daily) plus prophylactic-dose low molecular weight heparin (LMWH) is the standard regimen for women meeting criteria for obstetric APS. 1, 2, 3
• Treatment should be started before 16 weeks gestation and continued through delivery. 2, 3
• Typical LMWH dosing: enoxaparin 40 mg subcutaneously daily or dalteparin 5,000 units subcutaneously daily. 3
• Hydroxychloroquine should be continued throughout pregnancy to reduce pregnancy complications. 4, 2, 3

Thrombotic APS During Pregnancy

• Therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and for 6-12 weeks postpartum is required for women with prior thrombotic events. 2, 3
• Warfarin is contraindicated during pregnancy due to teratogenicity; switch to LMWH before conception or immediately upon pregnancy confirmation. 2

Non-Criteria Obstetric APS

• For 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 not recommended unless high-risk features are present (triple-positive antibodies, strongly positive lupus anticoagulant, advanced maternal age, or IVF pregnancy). 3

Assisted Reproductive Technology

• Prophylactic LMWH should be started at the beginning of ovarian stimulation, withheld 24-36 hours prior to oocyte retrieval, and resumed following retrieval due to increased thrombosis risk from elevated estrogen levels. 1, 3
• For patients with thrombotic APS undergoing ART, therapeutic anticoagulation is strongly recommended. 3

Pregnancy Monitoring Protocol

• Monthly clinical assessments and serial fetal ultrasounds with Doppler starting at 16-20 weeks are essential. 3
• Blood pressure checks at every visit to detect preeclampsia, which occurs 2.3-fold more frequently in APS. 3
• Monthly third-trimester Doppler assessments beginning at 28 weeks, increasing to every 1-2 weeks after 32 weeks. 3
• Laboratory monitoring (complete blood count, urinalysis with protein-to-creatinine ratio, serum creatinine, complement C3/C4) at least once per trimester. 3

Catastrophic APS

Catastrophic APS requires aggressive multimodal therapy combining anticoagulation, high-dose glucocorticoids, and plasma exchange. 4, 1, 3

Treatment Algorithm

• Immediate therapeutic anticoagulation with unfractionated heparin or LMWH. 4
• High-dose intravenous glucocorticoids (methylprednisolone 500-1000 mg daily for 3-5 days, then oral prednisone 1 mg/kg/day). 4
• Plasma exchange is associated with improved patient survival in retrospective studies and should be initiated promptly. 4, 1
• Rituximab has shown potential efficacy in recent anecdotal reports for catastrophic APS. 4
• Eculizumab (complement C5 inhibitor) has emerging evidence for efficacy, as complement activation is involved in tissue injury induced by antiphospholipid antibodies. 4
• Intravenous cyclophosphamide (500-1000 mg/m² monthly) should be added if catastrophic APS occurs in the setting of SLE flare. 3

Asymptomatic Antiphospholipid Antibody Carriers

• Low-dose aspirin (75-100 mg daily) is recommended for asymptomatic patients with high-risk antibody profiles (triple-positive, double-positive, or isolated lupus anticoagulant at high titers). 1, 2
• Hydroxychloroquine may be considered in asymptomatic carriers, particularly those with concomitant autoimmune disease. 2
• Aggressive cardiovascular risk factor modification (smoking cessation, blood pressure control, lipid management) is essential. 4
• Estrogen-containing contraceptives are absolutely contraindicated due to increased thrombosis risk; intrauterine devices and progestin-only pills are recommended alternatives. 1

Refractory APS

For patients who experience recurrent thrombosis despite therapeutic anticoagulation:

• Increase target INR range (e.g., from 2.0-3.0 to 3.0-4.0 for venous events). 3
• Add low-dose aspirin to warfarin if not already prescribed. 1
• Add hydroxychloroquine as adjunctive therapy. 2, 3
• Consider rituximab for refractory cases, though evidence is limited. 4

APS Nephropathy

• Long-term anticoagulation with warfarin is reasonable for APS nephropathy, as anticoagulated patients show higher complete response rates (59.5% vs. 30.8%) compared with those receiving immunosuppression alone. 4
• Direct oral anticoagulants are not recommended, as they are inferior to warfarin in preventing thromboembolic events in this setting. 4
• Patients should be co-managed with an experienced hematologist. 1

Common Pitfalls and Caveats

• Never use DOACs in triple-positive patients—this is associated with significantly increased thrombotic risk, particularly stroke. 1, 2, 3
• Do not discontinue anticoagulation prematurely—antibodies typically persist and thrombotic risk remains elevated lifelong. 1, 2
• INR monitoring may be unreliable in patients with lupus anticoagulant due to interaction between the antibody and thromboplastin reagent; consider chromogenic factor X assay for more accurate assessment. 5
• Do not withhold anticoagulation in sepsis unless active bleeding or critically low platelets; the prothrombotic state of sepsis may synergize with APS thrombotic risk. 3
• Aspirin does not typically complicate delivery or anesthesia—do not discontinue before delivery solely due to anesthesia concerns. 3
• High-intensity warfarin (INR >3.0) does not provide additional benefit over moderate-intensity therapy for venous events and increases bleeding risk. 1, 6
• Ensure proper overlap of parenteral anticoagulation (minimum 5 days and INR ≥2.0 for 24 hours) when initiating warfarin therapy. 2
• Confirmation of antiphospholipid antibodies requires repeat testing at least 12 weeks apart—do not base treatment decisions on a single positive test. 2, 3