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 Management

Diagnostic Criteria

Antiphospholipid syndrome requires both persistent laboratory evidence (positive antibodies on two occasions at least 12 weeks apart) AND clinical manifestations (thrombotic events or pregnancy morbidity). 1, 2

Laboratory Testing

• Test for all three antibodies: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti-β2 glycoprotein-I antibodies (aβ2GPI) 1, 2
• Antibodies must be detected on two separate occasions at least 12 weeks apart to confirm persistence 1, 2
• The 2023 ACR/EULAR criteria define moderate-titer thresholds at 40 Units and high-titer at 80 Units 2
• Triple positivity (all three antibodies positive) confers the highest thrombotic risk 2, 3
• Defer testing until at least 4-6 weeks after acute thrombosis, as protein levels may be transiently altered during acute events 1, 3

Clinical Criteria

• Thrombotic events: Arterial or venous thrombosis in any tissue or organ 1, 2
• Pregnancy morbidity: Recurrent pregnancy loss (≥3 unexplained consecutive miscarriages before 10 weeks), one or more unexplained fetal deaths at or beyond 10 weeks, or premature birth before 34 weeks due to preeclampsia or placental insufficiency 1, 2

When to Test

• Consider testing in patients with cryptogenic stroke AND a history of prior venous thromboembolism, second trimester abortion, or rheumatologic disorder 1
• In younger patients (<50 years) with unexplained thrombosis 1
• Do not routinely test older populations with multiple vascular risk factors, as there is no evidence supporting systematic testing 1

Treatment for Thrombotic APS

Confirmed APS with Prior Thrombosis

For patients with confirmed APS and prior thrombotic events, warfarin with target INR 2.0-3.0 is the gold standard anticoagulation therapy. 1, 2, 3, 4

• Warfarin should be continued indefinitely for patients with documented APS and thrombosis 4, 5
• Target INR of 2.0-3.0 provides optimal balance between thrombosis prevention and bleeding risk 1, 2, 3
• High-intensity warfarin (INR 3.0-4.5) should be avoided as it increases bleeding risk without additional benefit 3, 6
• For arterial thrombosis specifically, warfarin with target INR 2.0-3.0 is reasonable, with or without low-dose aspirin 1, 6

Critical Warning About DOACs

Rivaroxaban and other direct oral anticoagulants (DOACs) are contraindicated in triple-positive APS patients due to significantly increased thrombotic events compared to warfarin. 1, 2

• This harm is particularly pronounced in triple-positive patients but extends to all APS patients with prior thrombosis 1
• If a patient is already on a DOAC, transition immediately to warfarin 2, 3
• Observational data suggest high recurrent thrombosis rates with all DOACs in APS 1

Isolated Positive Antibodies Without APS Criteria

• For patients with isolated antiphospholipid antibodies who do NOT meet full APS criteria, antiplatelet therapy alone (aspirin 75-100 mg daily) is recommended 1, 3
• These patients should not receive anticoagulation unless they develop thrombosis 1

Treatment for Obstetric APS

Confirmed Obstetric APS (Recurrent Pregnancy Loss)

For patients meeting criteria for obstetric APS, combined therapy with low-dose aspirin (81-100 mg daily) PLUS prophylactic-dose low molecular weight heparin (LMWH) is strongly recommended throughout pregnancy. 2, 3

• Start aspirin before 16 weeks gestation and continue through delivery 2
• LMWH should be used at prophylactic doses (e.g., enoxaparin 40 mg daily subcutaneously) 2
• Continue anticoagulation for 6 weeks postpartum due to persistent thrombotic risk 2

Thrombotic APS During Pregnancy

For pregnant women with a history of thrombotic APS, use therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum. 2, 3

• Therapeutic LMWH dosing (e.g., enoxaparin 1 mg/kg twice daily) is required 2
• Monitor anti-Xa levels to ensure therapeutic anticoagulation 2
• Warfarin is contraindicated during pregnancy due to teratogenicity 2

Adjunctive Therapy

• Adding hydroxychloroquine to standard therapy is conditionally recommended for patients with primary APS, as recent studies suggest decreased pregnancy complications 2

Primary Prevention in Asymptomatic Patients

For asymptomatic patients with persistently positive moderate-to-high titer antiphospholipid antibodies (especially triple-positive or with lupus anticoagulant), low-dose aspirin 75-100 mg daily is recommended for primary prevention. 2, 3

• This is particularly important in patients with additional cardiovascular risk factors 3, 6
• Aggressively manage hypertension, hyperlipidemia, and diabetes, as these significantly amplify thrombotic risk 3

Management of Refractory or Catastrophic APS

Refractory APS (Recurrent Thrombosis Despite Anticoagulation)

• Consider increasing target INR range (though evidence is limited) 2
• Add hydroxychloroquine as adjunctive therapy 2
• Consider adding low-dose aspirin to warfarin if not already prescribed 6

Catastrophic APS

Catastrophic APS requires aggressive triple therapy: anticoagulation PLUS high-dose glucocorticoids PLUS plasma exchange. 2

• Add intravenous immunoglobulins if initial response is inadequate 2, 6
• If occurring in the setting of SLE flare, add intravenous cyclophosphamide (500-1000 mg/m² monthly) 2
• Early recognition and treatment are critical to reduce mortality 6

Critical Pitfalls to Avoid

• Never abruptly discontinue anticoagulation in APS patients, as this dramatically increases thrombotic risk 3
• Avoid oral contraceptives and pregnancy without appropriate anticoagulation, as both significantly increase thrombotic risk 5
• Do not use prednisone alone for thrombosis prevention in APS—it is ineffective and increases recurrence rates 5
• INR monitoring may be unreliable during acute illness or sepsis due to hepatic dysfunction; do not withhold anticoagulation based on INR alone in these settings 2
• Do not diagnose APS based on a single positive antibody test—persistence over 12 weeks is mandatory 1, 2