What is antiphospholipid syndrome?

What is Antiphospholipid Syndrome?

Antiphospholipid syndrome (APS) is a thrombo-inflammatory autoimmune disease driven by antiphospholipid antibodies (aPL) that recognize phospholipid surfaces and phospholipid-binding proteins, leading to thrombosis, pregnancy morbidity, and other autoimmune and inflammatory manifestations. 1

Pathophysiology

APS is fundamentally an antibody-mediated disease where pathogenic autoantibodies trigger specific cellular inflammatory and thrombotic pathways 2:

• Anti-β2-glycoprotein I antibodies are the critical pathogenic antibodies that induce endothelial cell activation, cytokine release, and create a prothrombotic state 2, 3
• The antibodies activate complement, neutrophils, and platelets, leading to neutrophil extracellular trap formation and subsequent thrombin generation 4
• An oxidized low-density lipoprotein (oxLDL)-β2GPI complex induces macrophage differentiation to foam cells, contributing to atherothrombosis 4

Clinical Manifestations

The clinical features are not specific for APS, making laboratory confirmation essential 1:

Thrombotic Manifestations

• Venous and arterial thrombosis affecting any vascular bed, predominantly in young adults 4
• Cardiovascular events are the leading causes of morbidity and mortality in APS 4
• Neurological symptoms including stroke, particularly in younger patients 1

Obstetric Manifestations

• Recurrent pregnancy loss, particularly second- or third-trimester miscarriages 1
• Late pregnancy loss is more strongly associated with specific antibody profiles than early pregnancy loss 5

Other Manifestations

• Thrombocytopenia 1
• Cardiac valve alterations 1
• Livedo reticularis 1
• Painful leg ulcerations 1

Diagnostic Criteria

The diagnosis of APS requires one clinical criterion (vascular thrombosis or pregnancy morbidity) AND one laboratory criterion (persistent presence of aPL). 6

Laboratory Testing Requirements

Three key antiphospholipid antibodies must be tested: 5

• Lupus anticoagulant (LA)
• Anticardiolipin antibodies (aCL) IgG and IgM
• Anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG and IgM

Two consecutive positive tests at least 12 weeks apart are mandatory to confirm persistent positivity and exclude transient antibody presence 6, 5

Laboratory Methodology

LA testing requires a rigorous 3-step approach 5:

• Screening test
• Mixing study
• Confirmation test
• Both APTT and dilute Russell's viper venom time (dRVVT) must be performed in parallel - omitting either test increases risk of underdiagnosis in up to 55% of triple aPL-positive samples 5

aCL and aβ2GPI measurement 5:

• Must be performed by solid phase assays (ELISA)
• Positivity defined as values above the 99th percentile of normal controls
• Medium/high titer antibodies (>40 Units) are of utmost importance for diagnosis 5
• The 2023 ACR/EULAR criteria set moderate and high titer thresholds at 40 and 80 Units respectively, abandoning the 99th percentile cutoff calculation 1

Risk Stratification

Triple positivity (LA, aCL, and aβ2GPI) carries the highest thrombotic risk and identifies high-risk patients requiring aggressive management 6, 5:

• IgG isotype antibodies are clinically more relevant than IgM isotypes 5
• However, in obstetric APS, isolated aCL or aβ2GPI IgM is more frequent and represents an independent risk factor 1
• Concordance of isotype (same isotype for aCL and aβ2GPI) reinforces clinical probability 1

Additional Risk Factors

• Co-existence with systemic lupus erythematosus (SLE) - approximately 30% of SLE patients have antiphospholipid antibodies 5
• Traditional cardiovascular risk factors (smoking, hypertension, hyperlipidemia, obesity) significantly increase thrombotic risk 4, 7

Classification vs. Clinical Diagnosis

A critical distinction exists between classification criteria and clinical diagnosis 1:

• Classification criteria are strict, meant for research participant inclusion to study homogeneous populations
• Clinical diagnosis is broader, meant to diagnose each APS patient to optimize management
• Patients diagnosed with APS may or may not fulfill classification criteria
• Inappropriate use of classification criteria may lead to misdiagnosis or underdiagnosis 1

Catastrophic Antiphospholipid Syndrome (CAPS)

CAPS is a rare, severe variant characterized by 8, 3:

• Rapid-onset, widespread thrombosis leading to multi-organ failure
• Commonly affects kidneys, lungs, central nervous system, and heart
• Often triggered by infections, surgical procedures, or cessation of anticoagulation
• High mortality rate, though recent treatment advances have improved survival 3

CAPS requires early implementation of triple therapy: 5

• Anticoagulation
• High-dose glucocorticoids
• Plasma exchange

Emerging therapies include eculizumab (complement inhibitor) and rituximab for refractory cases 5

Associated Conditions

APS can occur as 8:

• Primary APS - not associated with other disorders
• Secondary APS - associated with conditions such as systemic lupus erythematosus or other rheumatological disorders 1

Patients with SLE and APS have worse outcomes compared to those with primary APS 5

Common Pitfalls

• Do not rely on classification criteria alone for clinical diagnosis - this leads to underdiagnosis 1
• Do not test for aPL during acute thrombotic events or infections - transient antibodies may cause false positives
• Do not omit either APTT or dRVVT in LA testing - this misses over half of triple-positive cases 5
• Do not ignore traditional cardiovascular risk factors - these significantly amplify thrombotic risk and must be aggressively controlled 4, 7
• LA testing during anticoagulation may be unreliable and requires special procedures 5