What is Antiphospholipid Antibody Syndrome (APS)?

Antiphospholipid Antibody Syndrome (APS)

Antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder characterized by recurrent thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). 1, 2

Definition and Classification

APS can be classified as:

• Primary APS: Occurs without any underlying disease
• Secondary APS: Associated with another autoimmune disorder, most commonly systemic lupus erythematosus (SLE) 3
• Catastrophic APS (CAPS): A rare, life-threatening variant characterized by multiple organ thrombosis developing over a short period, leading to multi-organ dysfunction and failure 4

Pathophysiology

APS is driven by antiphospholipid antibodies that target phospholipid-binding plasma proteins, particularly:

• Beta-2-glycoprotein I (β2GPI)
• Prothrombin
• Other phospholipid-binding proteins 1, 3

These antibodies promote a prothrombotic state through multiple mechanisms:

• Endothelial cell activation
• Platelet activation
• Complement activation
• Disruption of natural anticoagulant pathways 3, 4

Laboratory Diagnosis

The diagnosis of APS requires the detection of persistent aPL. The three standard laboratory tests include:

1. Lupus Anticoagulant (LA):

   • Functional coagulation assay requiring a 3-step methodology: screening, mixing, and confirmation
   • Two parallel phospholipid-dependent coagulation tests are recommended (dRVVT and LA-sensitive APTT) 2

2. Anticardiolipin Antibodies (aCL):

   • Measured by solid-phase assays (ELISA or automated systems)
   • Both IgG and IgM isotypes must be measured
   • Must be β2GPI-dependent to avoid detection of non-pathogenic antibodies 2

3. Anti-β2 Glycoprotein I Antibodies (aβ2GPI):

   • Measured by solid-phase assays (ELISA or automated systems)
   • Both IgG and IgM isotypes must be measured 2

For definitive diagnosis, the same antibodies must be positive on two separate occasions at least 12 weeks apart to rule out transient antibody positivity 2.

Risk Stratification

The risk profile is determined by the antibody pattern:

• Triple positivity (positive for LA, aCL, and aβ2GPI): Highest risk for thrombosis and pregnancy morbidity 1, 2
• Double positivity (especially aCL and aβ2GPI with concordant isotype): Intermediate risk 2
• Single LA positivity: Lower thrombotic risk than triple positivity 1, 2
• IgG isotypes: Generally have greater clinical relevance than IgM isotypes 2

Clinical Manifestations

Thrombotic APS

• Venous thrombosis (deep vein thrombosis, pulmonary embolism)
• Arterial thrombosis (stroke, myocardial infarction)
• Small vessel thrombosis affecting any organ system 5

Obstetric APS

• Recurrent early pregnancy losses (<10 weeks)
• Fetal death (≥10 weeks)
• Premature birth (<34 weeks) due to severe preeclampsia, eclampsia, or placental insufficiency 2

Non-criteria Manifestations

• Thrombocytopenia
• Hemolytic anemia
• Heart valve disease
• Renal microangiopathy
• Neurologic disorders (migraine, seizures, cognitive dysfunction) 5

Catastrophic APS (CAPS)

CAPS is characterized by:

• Rapid development of thrombosis in multiple organs
• Predominantly affecting small vessels
• Leading to multi-organ dysfunction and failure
• High mortality rate (30-50%) 6, 4

Common triggers include:

• Infections
• Surgeries
• Trauma
• Medication changes
• Malignancy 4

Management Considerations

For aPL-positive patients without thrombosis:

• Aggressive management of traditional cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, smoking) 6
• Low-dose aspirin may be considered in high-risk patients 3

For thrombotic APS:

• Long-term anticoagulation with vitamin K antagonists (target INR 2.0-3.0 for first venous event, higher for arterial or recurrent events) 3, 5
• Novel oral anticoagulants are generally not recommended as first-line therapy 5

For obstetric APS:

• Low-dose aspirin plus prophylactic low molecular weight heparin during pregnancy 3
• Continue until 6 weeks postpartum 3

For refractory or catastrophic APS:

• Combination therapy including:
  • Therapeutic anticoagulation
  • High-dose glucocorticoids
  • Plasma exchange
  • Intravenous immunoglobulin
  • Consider rituximab in refractory cases 4

Important Caveats

• Testing should ideally be performed before starting anticoagulation 2
• Results should be interpreted according to local cutoff values, with caution for low positive results 2
• Classification criteria (used for research) are stricter than diagnostic criteria used in clinical practice 2
• Traditional cardiovascular risk factors can exacerbate thrombotic risk in APS patients and should be aggressively managed 6
• Despite adequate anticoagulation, the risk of recurrent thrombosis remains high 5

APS requires careful diagnosis and long-term management to prevent potentially life-threatening thrombotic events and pregnancy complications.