What is Antiphospholipid Syndrome?
Antiphospholipid syndrome (APS) is a thrombo-inflammatory autoimmune disease driven by antiphospholipid antibodies that recognize phospholipid surfaces and phospholipid-binding proteins, causing thrombosis (blood clots in veins and/or arteries), pregnancy complications, and other inflammatory manifestations. 1
Core Pathophysiology
The disease mechanism involves antiphospholipid antibodies (aPL) that trigger multiple prothrombotic pathways: 1
- Inhibition of prostacyclin formation (reduces natural anticoagulation) 2
- Impaired protein C activation (disrupts anticoagulant mechanisms) 2
- Platelet activation and aggregation 2
- Limitation of endothelium-derived relaxing factor production (promotes vasoconstriction) 2
- Inhibition of fibrinolysis (prevents clot breakdown) 2
- Endothelial cell activation and dysfunction leading to a heightened procoagulant state 3, 4
Clinical Manifestations
Thrombotic Features
APS causes both venous and arterial thrombosis: 1, 2
- Venous thrombosis: Deep vein thrombosis, pulmonary embolism 2
- Arterial thrombosis: Stroke, myocardial infarction, peripheral arterial occlusion 2, 5
- Microvascular thrombosis: Can affect kidneys, lungs, central nervous system, heart 4
Obstetric Features
Pregnancy-related complications include: 1, 2
- Recurrent pregnancy loss (early or late) 2
- Preeclampsia 2
- Placental insufficiency 2
- Intrauterine growth restriction 2
Non-Thrombotic Manifestations
Additional clinical features that help identify APS: 2, 5
- Thrombocytopenia (low platelet count) 2
- Livedo reticularis (mottled skin discoloration) 2, 5
- Cardiac valve abnormalities 2
- Neurological manifestations: Epilepsy, cognitive dysfunction 2, 5
- Autoimmune hemolytic anemia 5
Diagnostic Requirements
Diagnosis requires BOTH clinical criteria AND laboratory criteria—the clinical features alone are not specific for APS. 1
Clinical Criteria (at least one required):
- Vascular thrombosis: One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ 2, 6
- Pregnancy morbidity: Specific patterns of pregnancy loss or complications 2, 6
Laboratory Criteria (at least one required, confirmed on two occasions ≥12 weeks apart):
The cornerstone antibodies are: 1, 2
- Lupus anticoagulant (LA) 1, 2
- Anticardiolipin antibodies (aCL) IgG and/or IgM 1, 2
- Anti-β2 glycoprotein I antibodies (aβ2GPI) IgG and/or IgM 1, 2
The 2023 ACR/EULAR criteria define moderate titer as ≥40 Units and high titer as ≥80 Units, abandoning the 99th percentile cutoff approach. 1
Risk Stratification by Antibody Profile
Triple positivity (positive for all three antibodies: LA, aCL, and aβ2GPI) carries the highest thrombotic risk. 2, 6
- High-risk profiles: Lupus anticoagulant positive, double or triple antibody positivity, persistently high antibody titers 2
- Lower-risk profiles: Isolated anticardiolipin or anti-β2GPI antibodies at low-medium titers 2
- Persistent single-positive LA: Lower thrombotic risk than triple positivity but still significant 1
Primary vs. Secondary APS
APS can occur in two forms: 3, 5
- Primary APS: Occurs as an isolated condition without other autoimmune diseases 3, 5
- Secondary APS: Associated with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) 3, 5
When APS occurs with SLE, patients more frequently display arthralgias, arthritis, autoimmune hemolytic anemia, livedo reticularis, epilepsy, glomerular thrombosis, and myocardial infarction. 5
Catastrophic Antiphospholipid Syndrome (CAPS)
CAPS is a rare, life-threatening variant characterized by rapid-onset, widespread thrombosis leading to multi-organ failure. 3, 7, 4
- Rapid organ involvement: Kidneys, lungs, central nervous system, heart most commonly affected 4
- Small vessel occlusions with microthromboses 4
- High mortality rate despite treatment advances 3, 4
- Common triggers: Infections, surgical procedures, cessation of anticoagulation therapy 3, 4
- Predominantly affects younger patients and those with SLE 4
Important Clinical Caveats
The clinical features of APS are not specific for the disease—accurate diagnosis depends entirely on proper detection and interpretation of antiphospholipid antibodies. 1
Classification criteria (used for research) are distinct from diagnostic criteria used in routine clinical care—patients diagnosed with APS in clinical practice may not fulfill strict classification criteria, and inappropriate use of classification criteria can lead to underdiagnosis. 1
Testing must be repeated at least 12 weeks apart to confirm persistent antibody positivity, as transient antibodies can occur with infections and other conditions. 2, 6