What key topics should be covered in a seminar on antiphospholipid syndrome (APS)?

Seminar on Antiphospholipid Syndrome: Essential Topics

1. Definition and Pathophysiology

Antiphospholipid syndrome is an autoimmune disorder driven by antiphospholipid antibodies that recognize phospholipid surfaces and phospholipid-binding proteins, inducing thrombosis, pregnancy morbidity, and inflammatory manifestations through multiple mechanisms including inhibition of prostacyclin formation, protein C activation, platelet effects, and fibrinolysis inhibition. 1

• The pathophysiological hallmark is thrombosis, with complement activation playing an important contributory role 2
• APS can present as primary (isolated) or secondary (associated with other autoimmune diseases, especially systemic lupus erythematosus) 3

2. Diagnostic Criteria and Laboratory Testing

Core Laboratory Requirements

All three antiphospholipid antibody types—lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-β2 glycoprotein I antibodies (aβ2GPI) IgG/IgM—must be tested in parallel for every patient being evaluated for APS. 4

• Lupus anticoagulant testing requires a 3-step methodology (screening, mixing, confirmation) using BOTH activated partial thromboplastin time (APTT) AND dilute Russell's viper venom time (dRVVT) in parallel 5, 4
• Omitting either dRVVT or APTT increases the risk of missing the diagnosis in up to 55% of triple-positive patients and 31% of all APS patients 5, 6
• Critical pitfall: LA testing should NOT be performed during anticoagulation therapy as it causes false positives or false negatives 6

Antibody Thresholds and Persistence

• aCL and aβ2GPI positivity is defined as values above the 99th percentile of normal controls 5, 4
• The 2023 ACR/EULAR classification criteria define moderate titer as >40 Units and high titer as >80 Units 5, 1
• All positive antibody results must be repeated after at least 12 weeks (and no later than 5 years) to confirm persistence and exclude transient antibody presence 4

Risk Stratification by Antibody Profile

• Triple positivity (LA + aCL + aβ2GPI) carries the highest thrombotic risk and represents the most clinically significant antibody profile 1, 4
• Double positivity with concordant isotype (both aCL and aβ2GPI of the same isotype, particularly IgG) is a high-risk feature 4
• IgG isotype antibodies are clinically more relevant than IgM 4
• Isolated LA positivity confers lower thrombotic risk compared with triple positivity 4

Classification vs. Clinical Diagnosis

• The 2023 ACR/EULAR classification criteria are intended for research purposes and are more stringent than criteria used for routine clinical diagnosis 4
• Applying classification criteria in everyday practice leads to underdiagnosis and missed cases 4

3. Clinical Manifestations

Thrombotic Manifestations

• Thrombosis can affect any vascular bed: venous, arterial, and microvasculature 3, 7
• Arterial APS (e.g., stroke) carries a higher recurrence risk than venous APS 1
• Other manifestations include thrombocytopenia, livedo reticularis, cardiac valve abnormalities, and neurological manifestations 1, 8

Obstetric Manifestations

• Pregnancy morbidity criteria include: three or more consecutive losses prior to 10 weeks' gestation, one or more fetal losses at or after 10 weeks' gestation, and delivery at <34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress 1
• High-risk antiphospholipid antibody profiles increase the odds of fetal growth restriction by 4.7-fold and preeclampsia by 2.3-fold 1

Catastrophic APS (CAPS)

• CAPS is a rare, severe variant marked by rapid-onset, widespread thrombosis leading to multi-organ failure 9
• Often triggered by infections, surgical procedures, or cessation of anticoagulation therapy 9

4. Management of Thrombotic APS

Venous Thrombosis

Lifelong warfarin therapy targeting an INR of 2.0-3.0 is the standard of care for patients with documented venous thromboembolism and persistent antiphospholipid antibodies. 1

• INR should be checked at least monthly, with more frequent testing if unstable 1

Arterial Thrombosis

Two evidence-based regimens are recommended for arterial APS: high-intensity warfarin with target INR 3.0-4.0, OR moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin (≈81 mg daily). 1

Direct Oral Anticoagulants (DOACs)

Direct oral anticoagulants should be avoided in all APS patients, and rivaroxaban specifically is associated with excess recurrent arterial thrombosis compared with warfarin. 1

• If a triple-positive APS patient is already on a DOAC, transition to warfarin therapy 1

Primary Prevention

• For asymptomatic antiphospholipid antibody-positive patients, low-dose aspirin (75-100 mg daily) is recommended for primary prevention, especially in those with high-risk antibody profiles 1

5. Management of Obstetric APS

Standard Therapy

For patients meeting criteria for obstetric APS, combined therapy with low-dose aspirin (81-100 mg daily) and prophylactic-dose low molecular weight heparin is strongly recommended, starting before 16 weeks and continuing through delivery. 1

Thrombotic APS in Pregnancy

• For pregnant women with thrombotic APS, therapeutic-dose LMWH plus low-dose aspirin should be used throughout pregnancy and postpartum 1
• Therapeutic anticoagulation should be continued for 6-12 weeks postpartum in patients with thrombotic APS 1

Adjunctive Therapy

• The addition of hydroxychloroquine to standard therapy is conditionally recommended for patients with primary APS, as recent studies suggest it may decrease complications 1
• Hydroxychloroquine should be continued throughout pregnancy in patients who have both APS and SLE 1

Non-Criteria Obstetric APS

• For pregnant women with positive aPL who don't meet full APS criteria, prophylactic aspirin (81-100 mg daily) is conditionally recommended, starting before 16 weeks 1
• Routine prophylactic LMWH for all non-criteria obstetric APS patients is conditionally discouraged due to insufficient benefit and potential harms 1

High-Risk Features Justifying LMWH Addition

• Triple-positive antibody profile 1
• Strongly positive lupus anticoagulant 1
• Advanced maternal age 1
• Pregnancy achieved by in-vitro fertilization 1

6. Pregnancy Monitoring Protocol

Clinical Assessment

• Monthly clinical assessments with rheumatology or high-risk obstetric visits at least once per trimester 1
• More frequent visits (every 2-4 weeks) for triple-positive, lupus-anticoagulant-positive, or concurrent SLE patients 1
• Blood-pressure measurement at every prenatal visit is essential 1

Laboratory Monitoring

• Perform complete blood count, urinalysis with protein-to-creatinine ratio, serum creatinine, and complement C3/C4 levels at least once per trimester 1
• Anti-dsDNA antibodies should be checked in patients with concurrent SLE to differentiate disease flare from preeclampsia 1

Fetal Surveillance

• First-trimester ultrasound (11-14 weeks) to confirm viability and dating 1
• Detailed anatomic survey with Doppler (20-24 weeks) to establish baseline uterine and umbilical-artery flow 1
• Monthly third-trimester Doppler assessments beginning at 28 weeks (umbilical artery, uterine arteries, ductus venosus, middle cerebral artery) 1
• Increase surveillance to every 1-2 weeks after 32 weeks or sooner if abnormalities are detected 1
• Monthly fetal biometry in the third trimester to detect IUGR 1

7. Management of Catastrophic APS

Aggressive treatment with a combination of anticoagulation, high-dose glucocorticoids, and plasma exchange is recommended for catastrophic APS. 1

• Intravenous immunoglobulin should be added to the combination therapy 9
• If CAPS occurs in the setting of SLE flare, add intravenous cyclophosphamide (500-1000 mg/m² monthly) 1

8. Contraception in APS

Combined estrogen and progesterone contraceptives are contraindicated in women with positive antiphospholipid antibodies due to increased thrombotic risk. 5, 4

• Safe options include: copper IUD, progestin IUD, progestin implant, and progestin-only pills 5, 4

9. Assisted Reproductive Technology (ART)

• In subfertile patients with APS who desire pregnancy, ART should be deferred if disease is moderately or severely active 1
• For patients with obstetric APS undergoing ART, prophylactic anticoagulation with heparin or LMWH is strongly recommended 1
• For patients with thrombotic APS undergoing ART, therapeutic anticoagulation is strongly recommended 1
• Prophylactic LMWH should be started at the beginning of ovarian stimulation, withheld 24-36 hours prior to oocyte retrieval, and resumed following retrieval 1

10. Ongoing Monitoring and Follow-up

• For patients with confirmed APS, annual retesting of LA, aCL, and aβ2GPI is recommended to evaluate fluctuation of titers and changes in antibody profile over time 5, 4
• Regular monitoring of anticoagulation therapy is essential 1
• Patients with high-risk profiles (triple-positive or double-positive with LA) require more intensive anticoagulation and closer monitoring 1

11. Emerging Research Areas

Lupus Anticoagulant

• Whether single (dRVVT or aPTT) or double (dRVVT and aPTT) LA test positivity in triple aPL-positive patients contributes to higher risk 5
• Further studies needed on quantification of LA and the potential utility of LA strength in risk assessment 5

Non-Criteria Antibodies

• Further investigations on antiphosphatidylserine/prothrombin antibodies as dependent/independent of LA as a risk factor for thrombosis 5
• Evaluation of anti-domain I antibodies and their epitope specificity 5

Alternative Methods

• Harmonization in thrombin generation methodology for use in APS patients 5
• Combined use of thrombin generation and machine learning as a possible diagnostic aid 5