What is the diagnosis and treatment for a patient with suspected antiphospholipid syndrome, particularly those with a history of recurrent miscarriages and thrombotic events?

Antiphospholipid Syndrome: Diagnosis and Treatment

For patients with suspected antiphospholipid syndrome presenting with recurrent miscarriages and thrombotic events, confirm diagnosis with persistent antiphospholipid antibodies (tested twice, 12 weeks apart) and treat with warfarin (target INR 2.0-3.0) for thrombotic manifestations and combined low-dose aspirin plus prophylactic-dose low molecular weight heparin throughout pregnancy for obstetric manifestations. 1, 2, 3

Diagnostic Criteria

Laboratory confirmation requires:

• Testing for all three antibodies: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL ≥40 units), and anti-β2-glycoprotein-I antibodies (aβ2GPI ≥40 units) 2, 3, 4
• Positive results must be confirmed on repeat testing at least 12 weeks apart to exclude transient positivity 1, 2, 3
• Two positive LAC tests using different detection methods are necessary 3

Clinical criteria must include ONE of the following:

• Thrombotic events: Arterial or venous thrombosis in any tissue or organ 1, 5
• Obstetric complications: Three or more consecutive pregnancy losses before 10 weeks, one or more unexplained fetal deaths at/after 10 weeks, or one or more premature births before 34 weeks due to preeclampsia/eclampsia/placental insufficiency 2, 3

Risk stratification is critical:

• Triple-positive patients (all three antibodies positive) carry the highest risk for thrombotic and pregnancy complications 2, 3, 5
• LAC positivity is the strongest independent predictor of adverse pregnancy outcomes (relative risk 12.15) 3
• Double-positive or isolated high-titer antibodies represent intermediate risk 2

Treatment for Thrombotic APS

For venous thrombosis:

• Long-term anticoagulation with warfarin targeting INR 2.0-3.0 is the gold standard 1, 2, 6, 5
• Treatment duration: indefinite anticoagulation for patients with documented antiphospholipid antibodies and thrombosis 6
• Critical pitfall: Direct oral anticoagulants (DOACs), particularly rivaroxaban, are contraindicated in triple-positive APS due to excess thrombotic events compared to warfarin 1, 2, 3
• If a triple-positive patient is already on a DOAC, transition immediately to warfarin 2

For arterial thrombosis:

• Warfarin with target INR 2.0-3.0 is reasonable, though higher intensity (INR 3.0-4.0) may be considered for refractory cases 1, 2
• Anticoagulation may be superior to antiplatelet therapy for secondary prevention of arterial events 2

For isolated antiphospholipid antibodies without full APS criteria:

• Antiplatelet therapy alone (aspirin) is recommended over anticoagulation 1
• No differential stroke risk reduction was found with warfarin versus aspirin in patients with isolated antibodies 1

Treatment for Obstetric APS

For confirmed obstetric APS (meeting full diagnostic criteria):

• Combined therapy with low-dose aspirin (81-100 mg daily) starting before 16 weeks gestation AND prophylactic-dose low molecular weight heparin throughout pregnancy 2, 3, 7
• Continue LMWH postpartum for at least 6 weeks due to persistent thrombotic risk 3
• Consider adding hydroxychloroquine (200-400 mg daily) as recent studies suggest it may decrease complications 2, 3

For pregnant women with thrombotic APS:

• Therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum 2, 3
• This represents the highest-risk obstetric scenario requiring intensive anticoagulation 2

For positive antiphospholipid antibodies without meeting full obstetric APS criteria:

• Prophylactic aspirin alone (81-100 mg daily) starting before 16 weeks as preeclampsia prophylaxis 2, 3
• Do not routinely use prophylactic heparin unless additional high-risk features are present (triple-positive, advanced maternal age, IVF pregnancy) 2

Special Considerations

Assisted reproductive technology (ART):

• For obstetric APS patients undergoing ART: prophylactic LMWH starting at beginning of ovarian stimulation, withheld 24-36 hours prior to oocyte retrieval, then resumed 2
• For thrombotic APS patients undergoing ART: therapeutic anticoagulation throughout 2, 3

Catastrophic APS:

• Aggressive treatment with combination of anticoagulation, glucocorticoids, and plasma exchange 2
• Add intravenous cyclophosphamide (500-1000 mg/m² monthly) if occurring in setting of SLE flare 2

APS with sepsis:

• Continue therapeutic anticoagulation with warfarin (target INR 2.0-3.0) unless active bleeding or specific contraindication 2
• Sepsis itself is prothrombotic and may synergize with APS thrombotic risk, making anticoagulation even more critical 2
• Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low or there is active bleeding 2, 7

Critical Pitfalls to Avoid

• Never diagnose APS based on single positive test - transient antibodies are common and do not indicate true APS 3, 4
• Avoid combined estrogen-progestin contraceptives in women with positive antiphospholipid antibodies due to increased thrombotic risk 3, 8
• Do not use DOACs in triple-positive APS - they are associated with excess thrombotic events compared to warfarin 1, 2, 3
• Pregnancy and oral contraceptives significantly increase thrombotic risk in APS patients 8
• Testing for antiphospholipid antibodies in older populations with increasing vascular risk factors is not supported by evidence 1

Monitoring

• Regular INR monitoring for patients on warfarin, targeting 2.0-3.0 for most patients 1, 2, 6
• Anti-Xa monitoring for patients on heparin or LMWH 2
• Patients with high-risk profiles (triple-positive or double-positive with LAC) require closer monitoring 2