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

Diagnostic Criteria

Antiphospholipid syndrome requires both persistent laboratory findings (positive antiphospholipid antibodies on two occasions at least 12 weeks apart) AND clinical manifestations (thrombotic events or pregnancy morbidity including recurrent miscarriages). 1

Laboratory Testing

• Test for all three antibodies: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti-β2 glycoprotein-I antibodies (aβ2GPI) 2, 1
• Antibodies must be detected on two separate occasions at least 12 weeks apart to confirm persistence 1
• Moderate-to-high titers are defined as ≥40 Units, with high titers at ≥80 Units 1
• Triple positivity (all three antibodies positive) confers the highest thrombotic risk and mandates more aggressive treatment 1, 3
• Defer testing until at least 4-6 weeks after acute thrombotic events, as antibody levels may be transiently altered during acute phases 4

Clinical Criteria

• Thrombotic events: arterial or venous thrombosis in any tissue or organ 1
• Pregnancy morbidity: recurrent miscarriages (≥3 consecutive losses before 10 weeks, or ≥1 unexplained loss after 10 weeks), second trimester abortion, or preeclampsia 2, 1
• Consider testing in patients with cryptogenic stroke who have history of thrombosis, rheumatological disease, or recurrent pregnancy loss 2

Treatment for Thrombotic APS

Venous Thromboembolism

For patients with venous thrombosis and confirmed APS, long-term anticoagulation with warfarin targeting INR 2.0-3.0 is the gold standard treatment. 1, 4, 3

• Moderate-intensity warfarin (INR 2.0-3.0) provides optimal balance between thrombosis prevention and bleeding risk 4
• High-intensity warfarin (INR 3.0-4.5) should be avoided as it increases bleeding risk without additional benefit 4
• Avoid direct oral anticoagulants (DOACs), especially rivaroxaban, in triple-positive APS patients due to significantly increased thrombotic events compared to warfarin 2, 1, 4
• If a triple-positive patient is already on a DOAC, transition to warfarin immediately 1
• Anticoagulation should be continued long-term as the thrombotic risk persists 3, 5

Arterial Thrombosis

• Warfarin with target INR 2.0-3.0 is reasonable for secondary prevention of arterial events including stroke/TIA 2, 4
• Consider adding low-dose aspirin (75-100 mg daily) to warfarin for arterial events 3
• Some high-risk patients may require higher intensity anticoagulation (INR 3.0-4.0), though this must be balanced against bleeding risk 2

Isolated Antiphospholipid Antibodies Without APS Criteria

• For patients with positive antiphospholipid antibodies who do not fulfill full APS criteria (no thrombotic events or pregnancy morbidity), antiplatelet therapy with aspirin alone is recommended 2, 4
• No evidence supports warfarin over aspirin in this population 2

Treatment for Obstetric APS

Recurrent Pregnancy Loss

For women meeting criteria for obstetric APS (recurrent miscarriages with persistent antiphospholipid antibodies), combined therapy with low-dose aspirin (81-100 mg daily) plus prophylactic-dose low molecular weight heparin (LMWH) throughout pregnancy is strongly recommended. 1, 6

• Start treatment early, before 16 weeks gestation 1
• Continue treatment through delivery and postpartum period 1
• Adding hydroxychloroquine to standard therapy may further decrease pregnancy complications 1

Thrombotic APS in Pregnancy

• For pregnant women with prior thrombotic APS, use therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum 1
• Monitor with anti-Xa levels for patients on LMWH 1

Positive Antibodies Without Full APS Criteria

• For pregnant women with positive antiphospholipid antibodies who don't meet full APS criteria, start prophylactic aspirin (81-100 mg daily) before 16 weeks as preeclampsia prophylaxis 1
• Consider adding prophylactic heparin if additional high-risk features are present (triple-positive antibodies, advanced maternal age, IVF pregnancy) 1

Primary Prevention in Asymptomatic Patients

• For asymptomatic patients with persistently positive moderate-to-high titer antiphospholipid antibodies, low-dose aspirin (75-100 mg daily) is recommended for primary prevention, especially with high-risk antibody profiles (triple-positive or double-positive with LAC) 1, 4, 3
• Aggressively manage cardiovascular risk factors (hypertension, hyperlipidemia, diabetes) as these significantly amplify thrombotic risk 4
• Avoid oral contraceptives and hormone replacement therapy due to increased thrombotic risk 5

Catastrophic APS

• Aggressive treatment with combination of anticoagulation, high-dose glucocorticoids, and plasma exchange is recommended 1, 3
• Add intravenous cyclophosphamide (500-1000 mg/m² monthly) if catastrophic APS occurs in the setting of SLE flare 1
• Consider intravenous immunoglobulins as adjunctive therapy 3

Critical Management Pitfalls

• Never abruptly discontinue anticoagulation therapy as this significantly increases thrombosis risk 4
• The presence of thrombocytopenia (common in APS) does not reduce thrombotic risk and should not automatically preclude anticoagulation 6
• Pregnancy and oral contraceptive use significantly increase thrombotic risk in APS patients 5
• INR monitoring may be unreliable during acute illness or sepsis due to hepatic dysfunction 1
• Do not routinely repeat antibody testing once persistence is confirmed, unless clinical status changes 4