Antiphospholipid Syndrome (APS): Comprehensive Management
Diagnostic Criteria
APS diagnosis requires both clinical manifestations (thrombosis or pregnancy morbidity) AND persistent laboratory confirmation of antiphospholipid antibodies on two separate occasions at least 12 weeks apart. 1, 2
Laboratory Testing Requirements
All three key antibodies must be tested: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM 1
LAC testing requires a rigorous 3-step methodology: screening test, mixing study, and confirmatory test, using BOTH activated partial thromboplastin time (APTT) AND dilute Russell's viper venom time (dRVVT) in parallel 1
Critical pitfall: Omitting either APTT or dRVVT increases underdiagnosis risk in up to 55% of triple-positive samples 1
aCL and aβ2GPI measurement: Use solid-phase assays (ELISA or validated non-ELISA systems) for both IgG and IgM isotypes 3, 1
Positivity threshold: Values above the 99th percentile of normal controls, with the 2023 ACR/EULAR criteria defining moderate titer at ≥40 Units and high titer at ≥80 Units 1
Confirmation testing: Repeat all positive tests after 12 weeks to exclude transient antibody positivity and ensure test reliability 3
Clinical Criteria
Thrombotic manifestations: Any arterial or venous thrombosis in any tissue or organ 4
Pregnancy morbidity includes: 1
- Three or more consecutive pregnancy losses before 10 weeks' gestation
- One or more fetal deaths at or after 10 weeks' gestation
- Delivery before 34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress
Risk Stratification
Triple positivity (LAC + aCL + aβ2GPI all positive) represents the highest thrombotic risk and most clinically significant antibody profile. 3, 1
High-Risk Profiles
Triple-positive patients: Show strongest association with both thrombotic and obstetric APS, with highest risk of recurrent thrombosis or development of first thrombosis 3
Double-positive patients with concordant isotype: Both aCL and aβ2GPI of the same isotype (particularly IgG) confer high risk 1
LAC positivity alone: In obstetric APS and arterial thrombosis (myocardial infarction, stroke), LAC is the main predictor for thrombotic events and adverse pregnancy outcomes, independent of other aPL 3
Medium/high titer antibodies: Titers >40 Units or >99th percentile associated with higher risk 1
IgG isotype: Clinically more relevant than IgM 1
Lower-Risk Profiles
Double-positive patients (mostly LAC negative): Generally at lower risk, likely because aβ2GPI levels are insufficient to induce LAC positivity 3
Single-positive patients: LAC alone, aCL alone, or aβ2GPI alone are less likely to develop aPL-related events 3
Additional Risk Markers
Beta2GPI domain I antibodies (aD1): Strongly associated with thrombosis and useful for risk stratification confirmation, but do not add independent value beyond the current aPL panel 3
Antibodies to phosphatidylserine/prothrombin (aPS/PT): Mainly associated with LAC; additional diagnostic value needs confirmation 3
Treatment Strategies
Asymptomatic aPL-Positive Patients (No Prior Thrombosis or Pregnancy Loss)
Low-dose aspirin 75-100 mg daily for primary prevention, especially in high-risk antibody profiles (triple-positive or strongly positive LAC) 2
For pregnant women with positive aPL who do NOT meet criteria for obstetric or thrombotic APS: Prophylactic aspirin 81-100 mg daily starting before 16 weeks' gestation and continuing through delivery 3, 2
Thrombotic APS Management
For venous thrombosis, long-term anticoagulation with vitamin K antagonists (warfarin) targeting INR 2.0-3.0 is the standard of care. 2
Avoid direct oral anticoagulants (DOACs) in triple-positive APS patients due to increased risk of recurrent thrombotic events, especially arterial thrombosis and stroke 2
If a triple-positive patient is already on a DOAC: Transition to warfarin therapy 2
For arterial thrombosis: Consider higher intensity anticoagulation with INR 3.0-4.0 2
For refractory cases failing standard therapy: Consider increasing the target INR range 2
Obstetric APS Management
For patients meeting criteria for obstetric APS, combined therapy with low-dose aspirin (81-100 mg daily) AND prophylactic-dose heparin (usually low molecular weight heparin) is strongly recommended throughout pregnancy. 3, 2
For pregnant women with thrombotic APS: Use low-dose aspirin AND therapeutic-dose heparin (usually LMWH) throughout pregnancy and postpartum 3, 2
Hydroxychloroquine addition: Conditionally recommended as adjunctive therapy for patients with primary APS, as recent studies suggest decreased complications 3, 2
Timing of heparin discontinuation: Should be individualized by obstetrician-gynecologist and anesthesiologist based on specific clinical situation, typically held 24-36 hours before delivery for neuraxial anesthesia 3
Assisted Reproductive Technology (ART) in APS
Defer ART if disease is moderately or severely active 2
For obstetric APS patients undergoing ART: Prophylactic anticoagulation with heparin or LMWH 2
For thrombotic APS patients undergoing ART: Therapeutic anticoagulation 2
Timing: Start prophylactic LMWH at beginning of ovarian stimulation, withhold 24-36 hours prior to oocyte retrieval, resume following retrieval 2
Catastrophic APS (CAPS)
Aggressive combination therapy is mandatory: anticoagulation + high-dose corticosteroids + plasma exchange + intravenous immunoglobulin. 2, 5
Contraception Considerations
Combined estrogen-progesterone contraceptives are absolutely contraindicated in women with positive antiphospholipid antibodies due to increased thrombotic risk 3
Safe contraceptive options include: 3
- Copper IUD
- Progestin IUD
- Progestin implant
- Progestin-only pills
Monitoring and Follow-Up
Annual monitoring of LAC, aCL, and aβ2GPI to evaluate titer fluctuation and changes in antibody profile over time 1
SLE patients with APS: Monitor disease activity with clinical history, examination, and laboratory tests at least once per trimester during pregnancy, including complete blood count, differential, urinalysis, urinary protein:creatinine ratio, anti-DNA, C3, and C4 levels 3
Laboratory-clinician interaction is essential: Test results must be interpreted in clinical context with knowledge of anticoagulation status 3, 1
Inter-assay variability awareness: A sample testing positive in one assay does not automatically test positive in assays from different manufacturers or laboratories 3
Special Considerations for Children
While the provided evidence does not specifically address pediatric APS management, the diagnostic criteria and risk stratification principles apply. Children with confirmed APS require the same rigorous diagnostic confirmation with repeat testing at 12 weeks and should be managed with anticoagulation strategies similar to adults, with dose adjustments for weight and developmental considerations. 1, 2