What is antiphospholipid syndrome?

What is Antiphospholipid Syndrome?

Antiphospholipid syndrome (APS) is an autoimmune thromboinflammatory disease characterized by recurrent arterial or venous thrombosis and/or pregnancy complications (recurrent miscarriage, late fetal loss, or preterm delivery due to preeclampsia) occurring in patients with persistently positive antiphospholipid antibodies. 1, 2, 3

Core Pathophysiology

• APS is driven by pathogenic autoantibodies—primarily anti-β2 glycoprotein I antibodies—that trigger cell-specific inflammatory and thrombotic pathways through complex interactions with phospholipid-binding proteins and the coagulation cascade 4, 3
• The antibodies activate complement, cause endothelial cell dysfunction, and create a prothrombotic state that predisposes to both arterial and venous clots 2

Clinical Manifestations

Thrombotic Features

• Venous thrombosis can occur at any site, including deep vein thrombosis and pulmonary embolism 1
• Arterial thrombosis can occur at any site, most commonly presenting as stroke or myocardial infarction 1
• Microvascular thrombosis can lead to multi-organ involvement 2

Pregnancy-Related Complications

• Three or more consecutive pregnancy losses before 10 weeks' gestation 1
• One or more unexplained fetal deaths at or after 10 weeks' gestation 1
• Preterm delivery before 34 weeks due to severe preeclampsia, eclampsia, placental insufficiency, or intrauterine growth restriction 1

Non-Thrombotic Manifestations

• Thrombocytopenia (low platelet count) 5
• Neurological symptoms including cognitive dysfunction 2
• Cardiac valve disease 3
• Livedo reticularis (mottled skin discoloration) 3

Diagnostic Requirements

Both clinical manifestations AND persistent laboratory evidence are mandatory for diagnosis—neither alone is sufficient. 1

Required Laboratory Panel

• All three antibody types must be tested simultaneously: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-β2 glycoprotein I antibodies (aβ2GPI) IgG/IgM 1, 6
• Omitting any single test leads to underdiagnosis in up to 55% of high-risk patients 1, 6

Confirmation of Persistence

• Any positive antibody result must be repeated at least 12 weeks later (and no later than 5 years) to confirm persistence and exclude transient antibody positivity 1, 6
• This mandatory repeat testing distinguishes true APS from transient antibody elevations caused by infections or other triggers 6

Risk Stratification by Antibody Profile

Highest Risk: Triple Positivity

• Patients positive for all three antibodies (LA + aCL + aβ2GPI) carry the highest risk for thrombosis and pregnancy complications and require the most aggressive anticoagulation 1, 6

High Risk: Double Positivity with Concordant Isotype

• Both aCL and aβ2GPI positive for the same isotype (particularly IgG) significantly increases diagnostic reliability and thrombotic risk 1, 6

Moderate Risk: Single Positivity

• Isolated LA positivity confers lower thrombotic risk compared to triple positivity 1, 6

Isotype Considerations

• IgG antibodies are clinically more relevant than IgM antibodies 1, 6
• Isolated IgM positivity is considered less clinically significant 6

Classification: Primary vs. Secondary APS

• Primary APS occurs as an isolated condition without other autoimmune diseases 2, 3
• Secondary APS occurs in association with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) 2, 3
• Patients with SLE and APS have worse outcomes compared to those with primary APS 1

Catastrophic Antiphospholipid Syndrome (CAPS)

• CAPS is a rare, life-threatening variant characterized by rapid-onset widespread thrombosis leading to multi-organ failure 2
• Often triggered by infections, surgical procedures, or cessation of anticoagulation therapy 2
• Requires immediate intensive therapy combining anticoagulation, high-dose corticosteroids, plasma exchange, and intravenous immunoglobulin 2

Critical Diagnostic Pitfalls

• Classification criteria (2023 ACR/EULAR) are designed for research and are more stringent than clinical diagnostic criteria—using them for routine diagnosis leads to underdiagnosis and missed cases 1, 7, 6
• Clinical diagnosis should be broader to ensure all patients who need treatment are identified 1, 7
• LA testing should never be performed during anticoagulation therapy as it causes false positives or false negatives 7, 6
• Low-positive results near threshold values should be interpreted cautiously due to 10% assay imprecision 6

Treatment Principles

• Women with recurrent pregnancy loss should receive prophylactic-dose heparin plus aspirin 1
• Combined estrogen-progesterone contraceptives are absolutely contraindicated due to increased thrombotic risk 1
• Safe contraceptive options include copper IUD, progestin IUD, progestin implant, and progestin-only pills 1
• Treatment intensity is guided by antibody profile, with triple-positive patients requiring the most aggressive anticoagulation 1, 6

Long-Term Monitoring

• Annual retesting of LA, aCL, and aβ2GPI is recommended to evaluate titer fluctuations and changes in antibody profile over time 1, 7, 6
• Close collaboration between laboratory and clinician is essential for proper interpretation of results in the context of anticoagulation status 1, 6