What is antiphospholipid syndrome (APS) and how is it managed?

Antiphospholipid Syndrome (APS): Diagnosis and Management

Antiphospholipid syndrome (APS) is a thrombo-inflammatory autoimmune disorder characterized by persistent antiphospholipid antibodies (aPL) that can cause thrombosis, pregnancy morbidity, and other clinical manifestations requiring specific anticoagulation therapy based on clinical presentation.

Definition and Pathophysiology

• APS is an autoimmune disorder driven by antiphospholipid antibodies that recognize phospholipid surfaces and phospholipid-binding proteins, inducing thrombosis, pregnancy morbidity, and other inflammatory manifestations 1
• APS can occur as a primary condition or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) 2
• The pathophysiological mechanisms include inhibition of prostacyclin formation, protein C activation, effects on platelets, limiting endothelium-derived relaxing factor production, and inhibition of fibrinolysis 1

Clinical Manifestations

• Thrombotic manifestations: venous thromboembolism and arterial thrombosis (particularly stroke) are the most common and potentially life-threatening presentations 3
• Obstetric manifestations: recurrent pregnancy loss (typically second or third-trimester miscarriages), preeclampsia, and other pregnancy complications 1
• Other clinical features: thrombocytopenia, livedo reticularis, cardiac valve abnormalities, and neurological manifestations 1
• Catastrophic APS (CAPS): a rare, severe variant characterized by rapid-onset, widespread thrombosis leading to multi-organ failure, often triggered by infections, surgery, or anticoagulation cessation 2

Diagnostic Criteria

• Diagnosis requires both clinical criteria (thrombotic events or pregnancy morbidity) and laboratory criteria (persistent presence of aPL) 1
• Laboratory testing should include:
  • Lupus anticoagulant (LAC) - considered the strongest risk factor for adverse pregnancy outcomes 1
  • Anticardiolipin antibodies (aCL) 1
  • Anti-β2 glycoprotein-I antibodies (aβ2GPI) 1
• Antibodies must be detected on two or more occasions at least 12 weeks apart 1
• The 2023 ACR/EULAR classification criteria define moderate and high titer aPL thresholds at 40 Units and 80 Units respectively 1
• Triple positivity (positive for all three antibodies) indicates highest risk for thrombotic events 1

Management of Thrombotic APS

Primary Thromboprophylaxis (aPL-positive without prior thrombosis)

• For asymptomatic aPL-positive patients, low-dose aspirin (75-100 mg daily) is recommended for primary prevention, especially in those with high-risk antibody profiles 4
• In pregnant women with positive aPL who don't meet criteria for obstetric or thrombotic APS, prophylactic aspirin (81-100 mg daily) is conditionally recommended, starting before 16 weeks and continuing through delivery 1

Secondary Thromboprophylaxis (after thrombotic event)

• For venous thrombosis, long-term anticoagulation with vitamin K antagonists (warfarin) with a target INR of 2.0-3.0 is strongly recommended 4
• For arterial thrombosis, higher intensity anticoagulation (INR 3.0-4.0) may be considered 4
• Direct oral anticoagulants (DOACs) are not recommended for patients with arterial thrombosis or triple positive aPL 3
• Adjunctive therapies such as hydroxychloroquine and statins may be beneficial in complex cases with thrombotic recurrences or high bleeding risk 3

Management of Obstetric APS

• For patients meeting criteria for obstetric APS, combined therapy with low-dose aspirin and prophylactic-dose heparin (usually LMWH) is strongly recommended 1
• In pregnant women with thrombotic APS, low-dose aspirin and therapeutic-dose heparin (usually LMWH) should be used throughout pregnancy and postpartum 1
• The addition of hydroxychloroquine to standard therapy is conditionally recommended for patients with primary APS, as recent studies suggest it may decrease complications 1
• For refractory obstetric APS, there is insufficient evidence supporting increased LMWH dosing or intravenous immunoglobulin 1
• Prednisone is not recommended for obstetric APS as there are no controlled studies demonstrating benefit 1

Management of Catastrophic APS

• Aggressive treatment with a combination of anticoagulation, glucocorticoids, and plasma exchange is recommended 4
• A multidisciplinary approach is essential for this life-threatening condition 2

Monitoring and Follow-up

• Regular monitoring of anticoagulation therapy is essential, with anti-Xa monitoring for patients on heparin or LMWH 4
• Patients with high-risk profiles (triple-positive or double-positive with LAC) require more intensive anticoagulation and closer monitoring 4
• Pregnancy in APS patients requires additional monitoring due to increased risk of complications 1

Special Considerations

• White race has been associated with recurrent arterial events in APS patients 5
• Venous thrombosis occurs frequently during pregnancy or postpartum period (30% of women) and in women taking oral contraceptives 5
• Antiplatelet/anticoagulation therapy is recommended for NPSLE (neuropsychiatric systemic lupus erythematosus) related to antiphospholipid antibodies, especially for thrombotic cerebrovascular disease 1
• Anticoagulation may be superior to antiplatelet therapy for secondary prevention of arterial events in APS 1

Emerging Therapies

• New therapeutic strategies targeting thromboinflammatory pathways beyond anticoagulation are being investigated 6
• Personalized and targeted APS management approaches may become available in the near future 6