What is Antiphospholipid Syndrome (APS) and how is it managed?

Antiphospholipid Syndrome (APS): Definition and Management

Antiphospholipid Syndrome (APS) is a thrombo-inflammatory autoimmune disorder characterized by recurrent thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL), requiring long-term anticoagulation therapy for thrombotic events and specialized management for pregnancy complications.

Definition and Pathophysiology

APS is defined by:

• Persistent presence of antiphospholipid antibodies including:

  • Lupus anticoagulant (LA)
  • Anticardiolipin antibodies (aCL)
  • Anti-β2 glycoprotein I antibodies (aβ2GPI) 1

• Clinical manifestations:

  • Thrombotic events: Venous thrombosis (DVT, pulmonary embolism, cerebral venous thrombosis) and arterial thrombosis (stroke, myocardial infarction, peripheral arterial thrombosis) 2
  • Pregnancy morbidity: Recurrent fetal losses (especially in second and third trimesters), recurrent spontaneous abortions, and preterm birth due to preeclampsia 2
  • Other manifestations: Thrombocytopenia, cardiac valve abnormalities, livedo reticularis, and neurological symptoms 2

APS can occur as:

• Primary APS: Occurs independently
• Secondary APS: Associated with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) 3

Diagnosis

Diagnosis requires both clinical criteria and laboratory findings:

Laboratory Testing

• First-line testing should include all three antibodies 1:

  • Lupus anticoagulant (LA)
  • Anticardiolipin antibodies (aCL) - IgG and IgM isotypes
  • Anti-β2 glycoprotein I antibodies (aβ2GPI) - IgG and IgM isotypes

• Testing protocol:

  • Antibodies must be present on two or more occasions at least 12 weeks apart 1
  • LA testing requires specific methodology with screening, mixing, and confirmatory tests 1
  • Moderate and high titer thresholds for aCL and aβ2GPI are defined as 40 Units and 80 Units, respectively 1

Risk Stratification

• Triple positivity (positive for all three antibody types) carries the highest risk of thrombotic events
• Double positivity carries intermediate risk
• Single positivity carries the lowest risk 2

Management

Thrombotic APS

For patients with thrombotic APS, long-term anticoagulation with vitamin K antagonists (VKA) is the cornerstone of therapy 4:

• Venous thrombosis:

  • Warfarin with target INR 2.0-3.0 1, 4
  • Duration: Indefinite/lifelong anticoagulation due to high recurrence risk

• Arterial thrombosis:

  • Warfarin with target INR 2.0-3.0 plus low-dose aspirin, OR
  • Warfarin with higher intensity (INR 3.0-4.0) 4

• Direct oral anticoagulants (DOACs):

  • Not recommended for patients with arterial thrombosis or triple positive aPL 4
  • May be considered in select low-risk situations (e.g., patients with single venous thrombotic event and single aPL positivity) 4

Obstetric APS

For pregnant women with obstetric APS:

• Combination therapy with low-dose aspirin and prophylactic low molecular weight heparin (LMWH) 2
• Start aspirin preconceptionally and continue throughout pregnancy
• Start LMWH when pregnancy is confirmed 1
• Continue treatment until 6 weeks postpartum

Catastrophic APS (CAPS)

CAPS is a rare, life-threatening variant characterized by rapid-onset, widespread thrombosis leading to multi-organ failure 3:

• Treatment requires aggressive multidisciplinary approach:
  • Anticoagulation (usually heparin)
  • High-dose corticosteroids
  • Plasma exchange
  • Intravenous immunoglobulin 1, 3
  • Consider eculizumab in refractory cases 1

Additional Therapies

• Hydroxychloroquine: Beneficial in APS patients with SLE and may reduce thrombotic risk 4
• Statins: May be useful in complex settings due to anti-inflammatory properties 4
• Immunosuppression: May be considered for non-thrombotic manifestations or refractory cases 5

Special Considerations

Asymptomatic aPL Carriers

• Primary thromboprophylaxis: Low-dose aspirin is the first option 4
• Risk factor modification: Aggressive management of traditional cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, smoking) 6
• Avoid estrogen-containing contraceptives in women with positive aPL 2

Assisted Reproductive Technology (ART)

• For aPL-positive patients undergoing ART procedures:
  • Prophylactic anticoagulation with LMWH is recommended
  • Start at beginning of ovarian stimulation
  • Withhold 24-36 hours before oocyte retrieval
  • Resume following retrieval 1

Stroke in Young Patients with APS

• Comprehensive "heart to head" diagnostic approach
• Immediate referral to a stroke center
• Standard acute stroke protocols apply, including consideration for thrombolysis and thrombectomy
• Long-term anticoagulation with warfarin (target INR 2.0-3.0) 2

Monitoring and Follow-up

• Regular monitoring of aPL profiles
• Periodic assessment of cardiovascular risk factors
• Vigilance for signs of recurrent thrombosis
• Multidisciplinary approach involving rheumatology, hematology, and other specialists as needed

Common Pitfalls to Avoid

1. Misdiagnosis: Ensure proper testing protocol with confirmation of persistent antibodies at least 12 weeks apart
2. Inadequate anticoagulation: Maintain target INR range and avoid inappropriate use of DOACs in high-risk patients
3. Neglecting risk factor modification: Aggressively manage traditional cardiovascular risk factors
4. Overlooking non-thrombotic manifestations: APS can affect multiple organ systems beyond thrombosis
5. Delayed recognition of CAPS: Early recognition and aggressive treatment are crucial for survival