What causes high levels of antiphospholipid antibodies (aPL)?

Causes of High Antiphospholipid Antibodies (aPL)

Antiphospholipid antibodies arise primarily in autoimmune conditions (especially systemic lupus erythematosus), but also occur in infections, malignancies, drug exposures, and in otherwise healthy individuals without any identifiable underlying disease. 1

Primary Autoimmune Conditions

• Systemic Lupus Erythematosus (SLE) is the most common autoimmune disease associated with aPL, with approximately 37% of SLE patients testing positive for these antibodies 1, 2, 3
• Primary Antiphospholipid Syndrome (APS) occurs when aPL develop without any underlying autoimmune disease, representing a distinct autoimmune condition 4, 2
• Other rheumatic diseases including systemic sclerosis, Sjögren's syndrome, rheumatoid arthritis, and Behçet's disease can produce aPL 5

Infections

• Transient aPL positivity commonly occurs during acute infections, which is why confirmation testing at least 12 weeks apart is required for APS diagnosis 1
• Various bacterial, viral, and parasitic infections can trigger temporary antibody production 5

Malignancies

• Cancer patients frequently develop aPL, with certain types of aPL serving as markers of oncological progression 5
• Chronic asymptomatic aPL presence is particularly common in patients with malignancies 5

Drug-Induced aPL

• Certain medications can induce transient aPL production, requiring repeat testing after drug discontinuation to confirm persistence 1
• Drug-induced aPL typically resolve after medication cessation 1

Pregnancy-Related

• Approximately 6% of pregnant women without diagnosed APS test positive for aPL and are at risk for pregnancy complications including recurrent fetal loss, preeclampsia, intrauterine growth restriction, and fetal distress 1, 6
• aPL levels may fluctuate during pregnancy, with 25% of LA-positive patients becoming negative in the second or third trimester 1

Asymptomatic Carriers

• Healthy individuals can be carriers of aPL without any clinical manifestations, occurring in approximately 5.3% of normal obstetrical patients 6
• Chronic asymptomatic aPL presence is most common in elderly individuals and those with chronic diseases 5

Laboratory Considerations

The specific type and titer of aPL matters significantly for risk stratification:

• High-risk aPL profile includes lupus anticoagulant, double-positive (any combination of LA, anticardiolipin, or anti-β2-glycoprotein I), triple-positive (all three), or persistently high titers (≥40 units or ≥99th percentile) 1
• Low-risk aPL profile consists of isolated anticardiolipin or anti-β2-glycoprotein I antibodies at low-to-medium titers, particularly if transiently positive 1
• IgG isotype is generally more clinically significant than IgM, though IgM can be important in obstetric APS 1

Common Pitfalls

• Do not diagnose APS based on single positive test - persistence must be confirmed with repeat testing at least 12 weeks apart 1
• Timing of testing matters - aPL levels may decrease during acute thrombosis due to antibody deposition at the thrombotic site, and may fluctuate during pregnancy 1
• Anticoagulation interferes with LA testing - consider testing for antiphosphatidylserine/prothrombin antibodies as a surrogate when LA testing is unreliable 1
• Low positive results near cutoff values should be interpreted cautiously given assay imprecision of up to 10% 1