Antiphospholipid Syndrome: Diagnostic Criteria and Treatment
Diagnose APS using the 2023 ACR/EULAR classification criteria, which require both clinical manifestations (thrombosis or pregnancy morbidity) and persistent laboratory confirmation of antiphospholipid antibodies, then treat with long-term vitamin K antagonists for thrombotic APS and prophylactic anticoagulation plus low-dose aspirin for obstetric APS. 1
Diagnostic Criteria
Laboratory Testing Requirements
The cornerstone of APS diagnosis requires detection of three specific antiphospholipid antibodies 1:
Lupus anticoagulant (LA) - tested using two parallel assays:
- Dilute Russell's viper venom time (dRVVT)
- LA-sensitive activated partial thromboplastin time (APTT)
- Both screening AND confirmatory tests must be performed 1
Anticardiolipin antibodies (aCL) - measured by ELISA only:
- Moderate titer: ≥40 Units
- High titer: ≥80 Units 1
Anti-β2-glycoprotein I antibodies (aβ2GPI) - measured by ELISA only:
- Moderate titer: ≥40 Units
- High titer: ≥80 Units 1
Critical testing requirement: Antibodies must be persistently positive on two separate occasions at least 12 weeks apart 1. The 99th percentile cutoff calculation has been abandoned in favor of fixed thresholds 1.
Clinical Manifestations Required
At least one of the following clinical features must be present 1, 2:
Thrombotic events:
- Venous thrombosis (any site)
- Arterial thrombosis (any site)
- Small vessel thrombosis
Pregnancy morbidity:
- Three or more unexplained consecutive miscarriages before 10 weeks gestation
- One or more unexplained fetal deaths at or beyond 10 weeks gestation
- One or more premature births before 34 weeks due to eclampsia, preeclampsia, or placental insufficiency
Additional clinical features in 2023 criteria:
- Thrombocytopenia
- Cardiac valve disease
- Microvascular thrombosis 3
Important Diagnostic Pitfalls
Do not confuse classification criteria with clinical diagnosis - Classification criteria are designed for research with 99% specificity but only 84% sensitivity 3. In clinical practice, you must diagnose APS more broadly to optimize patient management 1. Patients may have genuine APS requiring treatment even if they don't meet strict classification criteria.
LA testing is mandatory - Omitting either dRVVT or APTT increases risk of missing diagnosis in up to 55% of triple-positive patients 1. Both tests must be performed simultaneously.
Avoid testing during anticoagulation - LA testing should be interpreted as absent with a comment on repeat testing when performed during vitamin K antagonist therapy, as this causes false negatives 1.
Risk Stratification
Triple-positive patients (LA + aCL + aβ2GPI all positive) have the highest thrombotic risk and require the most aggressive management 1, 4. Single-positive LA has lower risk than triple positivity but still requires treatment 1.
Treatment Approach
Thrombotic APS
For patients with thrombotic APS, use vitamin K antagonists (warfarin) as first-line long-term anticoagulation 4, 5. Target INR depends on thrombosis type:
- Venous thrombosis: Standard intensity anticoagulation
- Arterial thrombosis: Consider adding antiplatelet therapy or higher intensity anticoagulation 4
Avoid direct oral anticoagulants (DOACs) in high-risk patients, specifically:
DOACs have shown inferior outcomes in these populations and should not be used.
Obstetric APS
For women with obstetric APS (three or more pregnancy losses) who meet laboratory criteria, use prophylactic or intermediate-dose unfractionated heparin OR prophylactic low-molecular-weight heparin (LMWH) combined with low-dose aspirin (75-100 mg daily) throughout pregnancy and for at least 6 weeks postpartum 7.
LMWH is preferred over unfractionated heparin for both prevention and treatment of VTE in pregnancy 7.
For women on long-term warfarin attempting pregnancy: Switch to LMWH when pregnancy is confirmed rather than preemptively, using frequent pregnancy testing 7.
Catastrophic APS (CAPS)
This rare, life-threatening variant requires immediate intensive therapy 2, 8, 4:
- Anticoagulation with heparin
- High-dose corticosteroids (pulse therapy)
- Plasma exchange
- Intravenous immunoglobulin
CAPS presents with rapid-onset widespread microthrombosis causing multi-organ failure, often triggered by infection, surgery, or anticoagulation cessation 2, 8.
Key Management Principles
Continue anticoagulation indefinitely after thrombotic events - APS is a chronic thrombophilic condition requiring lifelong treatment 5.
Immunosuppressive therapy has limited role - Corticosteroids and immunosuppressants are not standard treatment except in CAPS or when APS coexists with active systemic lupus erythematosus 5.
Monitor for recurrent events - Ongoing surveillance is essential as APS manifestations can occur in episodes 9.