Antiphospholipid Syndrome (APS)

Definition

• Goldman-Cecil Medicine, p. 795
• Brenner and Rector's The Kidney, p. 1464

Historical Background

• Tietz Textbook of Laboratory Medicine, 7th Ed., p. (block 40)

Classification

• Primary APS: No associated autoimmune disease (30-55% of all APS patients)
• Secondary APS: Associated with SLE (aPL antibodies found in 25-75% of SLE patients) or other connective tissue diseases
• Catastrophic APS (CAPS): Rare, life-threatening form with multiple simultaneous vascular occlusions ("thrombotic storm"); often fatal
• Brenner and Rector's The Kidney, p. 1464
• Goldman-Cecil Medicine, p. 795

Antibody Profile (Diagnostic Criteria Tests)

1. Lupus anticoagulant (LA) - phospholipid-based clotting test (paradoxically prolongs aPTT in vitro, but is prothrombotic in vivo)
2. Anticardiolipin antibodies (aCL) - IgG and/or IgM isotype
3. Anti-β₂GPI antibodies - IgG and/or IgM isotype

• IgG isotype is more strongly associated with thrombosis than IgM
• LA is the strongest risk factor for thrombosis (6x higher risk of future thrombosis)
• aCL and anti-β₂GPI IgG are more correlated with thrombosis than IgM counterparts
• aPL antibodies found in up to 2% of normal individuals and in infections (HIV, HCV), but these are not usually associated with clinical APS
• "Seronegative APS": clinically suspected APS, negative for all three criteria antibodies - highlights need for additional biomarkers
• aPL may cause a false-positive VDRL test
• Tietz Textbook of Laboratory Medicine, 7th Ed.
• Brenner and Rector's The Kidney, p. 1464

Classification Criteria (Revised Sapporo / Sydney 2006)

Clinical Criteria

1. Vascular thrombosis: One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue/organ
2. Pregnancy morbidity:
   • One or more unexplained fetal deaths at or beyond 10 weeks' gestation
   • One or more premature births before 34 weeks due to eclampsia, severe preeclampsia, or placental insufficiency
   • Three or more unexplained consecutive spontaneous abortions before 10 weeks

Laboratory Criteria

• Positive for LA, aCL (IgG/IgM, medium or high titer), or anti-β₂GPI (IgG/IgM)
• Documented on 2 or more occasions at least 12 weeks apart, and within 5 years of clinical manifestations

Pathogenesis

1. "Two-hit" hypothesis: aPL antibodies alone may be insufficient; a "second hit" (pregnancy, oral contraceptives, nephrotic syndrome, SLE, hyperlipidemia, infection) may be required to trigger thrombosis
2. Procoagulant mechanisms of aPL antibodies:
   • Activation of endothelial cells, monocytes, and platelets
   • Interference with multiple coagulation factors: prothrombin, protein C, annexin V, factors VII and XII, tissue factor
   • Impaired fibrinolysis (inhibition of tissue plasminogen activator)
   • Inhibition of mTORC intracellular pathway
   • Complement activation (especially relevant in obstetric APS)
3. Net result: endothelial damage and intravascular coagulation
4. Genetic associations: HLA-DRB1 loci in SLE-associated APS

• Brenner and Rector's The Kidney, p. 1464

Clinical Features

Thrombotic Manifestations

Arterial Thrombosis

• Cerebrovascular events are the most common arterial complication: stroke, TIA, multi-infarct dementia, retinal artery occlusion
• Peripheral and intra-abdominal vascular occlusion (less common)

Cardiac

• Libman-Sacks endocarditis (nonbacterial valve vegetations) in ~1/3 of patients
• Pulmonary hypertension

Obstetric

• Recurrent spontaneous pregnancy loss
• Fetal growth retardation
• Placental thrombosis (mechanism)
• Preeclampsia, HELLP syndrome

Hematologic

• Thrombocytopenia (common)
• Prolonged aPTT (laboratory finding, paradoxical)
• Hemolytic anemia (less common)

Renal (APL Nephropathy)

• Thrombosis from glomerular capillaries to main renal artery and vein
• Arterial/arteriolar lesions: intimal mucoid thickening, subendothelial fibrosis, medial hyperplasia
• Glomerular: capillary thrombosis, mesangiolysis, GBM duplication (resembles TTP/HUS)
• Interstitial fibrosis and cortical atrophy from ischemia
• Found in ~40% of aPL-positive biopsied patients vs. only 4% without aPL antibodies
• Clinical features: proteinuria (sometimes nephrotic), active urinary sediment, hypertension, progressive renal dysfunction, renal infarction, renal vein thrombosis
• Important: biopsies may be misclassified as FSGS, membranous nephropathy, or MPGN

Renal biopsy in APS: organizing recanalized thrombi narrowing the lumens of two interlobular arteries, with ischemic-type glomerular tuft retraction (H&E, x200). - Brenner and Rector's The Kidney

• Brenner and Rector's The Kidney, pp. 1464-1466

Laboratory Findings

• Prolonged aPTT (due to LA activity)
• Thrombocytopenia
• False-positive VDRL
• Positive aCL, anti-β₂GPI, or LA (must be confirmed on a second occasion ≥12 weeks apart)

Treatment

Acute Thrombosis

• Managed similarly to thrombosis from other causes
• LMWH preferred when LA is present (avoids aPTT monitoring difficulties, since baseline aPTT is already prolonged)

Long-Term Anticoagulation

• Warfarin is the standard of care; target INR 2.0-3.0 for most patients
• Prolonged or indefinite therapy is generally required
• Direct oral anticoagulants (DOACs) are NOT as effective as warfarin in APS - this is a critical distinction from most other thrombophilias
• For first-episode VTE with positive aPL: indefinite anticoagulation is usually recommended (though evidence is limited)

Obstetric APS

• No established treatment has been shown to definitively prevent recurrent fetal loss
• Low-dose aspirin + heparin (LMWH or UFH) is commonly used in pregnancy

Catastrophic APS (CAPS)

• High-dose glucocorticoids
• Therapeutic anticoagulation
• Plasmapheresis and/or IVIG in refractory cases
• Goldman-Cecil Medicine, pp. 795-796

Prognosis

• Lupus anticoagulant carries the worst prognosis among aPL tests:
  • 6-fold higher risk of future thrombosis
  • 2-4 fold increased risk of recurrent thrombosis
  • 12% increased 10-year mortality
• SLE patients with IgG aCL have higher incidence of thrombosis and thrombocytopenia
• In one multicenter European study of 1000 SLE patients, thrombosis occurred in 7% over 5 years
• Goldman-Cecil Medicine, p. 795

Recent Evidence (2025)