Antiphospholipid Syndrome (APLA Syndrome)
Overview and Diagnosis
Antiphospholipid syndrome is an autoimmune thrombophilia requiring 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 Diagnosis
- All three criteria antibodies must be tested: lupus anticoagulant (LAC), anticardiolipin antibodies (aCL IgG/IgM), and anti-β2-glycoprotein I antibodies (aβ2GPI IgG/IgM). 1
- Lupus anticoagulant carries the highest thrombotic risk (relative risk ≈12 for adverse pregnancy outcomes) and is the strongest predictor of complications. 2, 1
- Triple positivity (all three antibodies positive) indicates the highest risk for thrombotic events and requires the most aggressive management. 1, 2
- Moderate-risk titers are ≥40 Units; high-risk titers are ≥80 Units per the 2023 ACR/EULAR criteria. 1, 2
Clinical Phenotypes
The syndrome presents in three distinct patterns that dictate entirely different treatment approaches: 2
- Asymptomatic aPL-positive (antibodies present, no clinical events)
- Obstetric APS (pregnancy morbidity only)
- Thrombotic APS (history of venous or arterial thrombosis)
Management of Thrombotic APS
Venous Thrombosis
For patients with venous thromboembolism (DVT or PE), lifelong warfarin targeting INR 2.0-3.0 is the standard of care. 1, 2
- Warfarin is strongly preferred over direct oral anticoagulants (DOACs), particularly in triple-positive patients. 1, 2
- DOACs should be avoided in all APS patients; rivaroxaban specifically is associated with excess recurrent arterial thrombosis compared with warfarin. 1, 2
- INR should be checked at least monthly, with more frequent testing if unstable. 2
Arterial Thrombosis
Arterial APS (e.g., stroke) carries higher recurrence risk and requires more intensive anticoagulation. 1
Two evidence-based regimens are recommended: 1
- High-intensity warfarin targeting INR 3.0-4.0, or
- Moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin (81 mg daily)
Refractory Cases
- For patients failing standard therapy, escalate to high-intensity warfarin (INR 3.0-4.0). 1, 2
- Consider adding hydroxychloroquine 200-400 mg daily as adjunctive therapy. 1, 2
Management of Obstetric APS
Confirmed Obstetric APS (≥3 Early Losses or ≥1 Late Loss)
Combined therapy with low-dose aspirin (81-100 mg daily) plus prophylactic-dose LMWH throughout pregnancy is strongly recommended. 1, 3, 2
Specific Dosing Protocol
- Aspirin: Start before 16 weeks gestation and continue through delivery. 1, 3, 2
- Prophylactic LMWH: Enoxaparin 40 mg SC once daily or dalteparin 5,000 units SC once daily. 3
- Duration: Throughout all three trimesters and continue for 6-12 weeks postpartum. 3
- Expected outcomes: This regimen yields ≈70% live-birth rates, but preeclampsia occurs in ~34% and preterm delivery in ~43% of treated patients. 3
Peripartum Management
- Hold LMWH at least 24 hours before planned delivery or neuraxial anesthesia. 3, 1
- Resume LMWH 6-12 hours after vaginal delivery or 12-24 hours after cesarean section once hemostasis is confirmed. 3, 1
- Continue aspirin throughout labor and delivery—it does not interfere with neuraxial anesthesia. 3, 1
Thrombotic APS in Pregnancy
For women with prior thrombotic events, therapeutic-dose LMWH plus low-dose aspirin is required throughout pregnancy and postpartum. 1, 3, 2
- Therapeutic dosing: Enoxaparin 1 mg/kg SC twice daily or dalteparin 100 units/kg SC twice daily. 3
- Rationale: Prior thrombosis adds substantial risk in the hypercoagulable pregnancy state. 3
- Postpartum: Continue therapeutic anticoagulation for 6-12 weeks minimum; the postpartum period carries the highest thrombotic risk. 3, 1
Asymptomatic aPL-Positive Women (No Clinical APS)
Aspirin alone (81-100 mg daily) started before 16 weeks and continued through delivery is recommended. 1, 3
- Routine prophylactic LMWH is not recommended for asymptomatic aPL-positive women. 1, 3
- The 2020 ACR guideline conditionally recommends against routine LMWH because evidence of benefit is insufficient and the drug carries known risks (bleeding, heparin-induced thrombocytopenia, osteoporosis). 3, 1
High-Risk Exceptions
LMWH may be considered only in very high-risk scenarios after shared decision-making: 1, 3
- Triple-positive antibody profile
- Strongly positive lupus anticoagulant
- Advanced maternal age
- IVF conception
Screening Recommendations
- Screen for antiphospholipid antibodies in women with ≥3 miscarriages before 10 weeks gestation (Grade 1B). 4
- Do not screen for inherited thrombophilia in women with pregnancy complications (Grade 2C). 4
- For women with two or more miscarriages but without APLA or thrombophilia, recommend against antithrombotic prophylaxis (Grade 1B). 4
Adjunctive Therapies
Hydroxychloroquine
- May be added to standard therapy (200-400 mg daily) for patients with primary APS; this is a conditional recommendation based on emerging data suggesting reduction in pregnancy complications. 1, 3, 2
- Should be continued throughout pregnancy in patients who have both APS and systemic lupus erythematosus. 1
- Should not be used in asymptomatic aPL-positive women without another indication (e.g., SLE). 3, 1
Therapies to Avoid
- Prednisone should be strongly avoided—no controlled trials demonstrate benefit and the risk profile is unfavorable. 3, 1
- Intravenous immunoglobulin and escalated LMWH doses have no demonstrated benefit in refractory cases. 3, 1
- Vitamin K antagonists (warfarin) are teratogenic in the first trimester and risk fetal intracranial hemorrhage after week 36. 3
Pregnancy Monitoring Protocol
Maternal Surveillance
- Rheumatology or high-risk obstetric visits at least once per trimester, with more frequent visits (every 2-4 weeks) for triple-positive, LAC-positive, or concurrent SLE patients. 1
- Blood pressure measurement at every prenatal visit—preeclampsia occurs ~2.3-fold more often in APS. 1
- Evaluate for thrombosis symptoms at each visit (limb swelling, chest discomfort, dyspnea, neurologic changes). 3
Laboratory Monitoring
- 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 in patients with concurrent SLE to differentiate disease flare from preeclampsia. 1
- Declining complement or rising anti-dsDNA titers signal increased risk of pregnancy loss, IUGR, and preterm birth. 1
Fetal Surveillance
Ultrasound Schedule
- 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 detected. 1
Key Doppler Parameters
- Umbilical-artery Doppler to detect placental insufficiency. 1
- Uterine-artery Doppler to assess abnormal placentation and predict preeclampsia risk. 1
- Cerebro-placental ratio in late-onset IUGR (≥34 weeks)—umbilical-artery Doppler alone is insufficient. 1
- Monthly fetal biometry in third trimester—IUGR occurs ~4.7-fold more frequently in high-risk APS. 1
Primary Prevention in Asymptomatic Patients
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 (triple-positive, high titers, or LAC-positive). 1, 2
Special Considerations
Pre-eclampsia Prophylaxis
- For women at risk for pre-eclampsia, low-dose aspirin throughout pregnancy starting from the second trimester is recommended over no treatment (Grade 1B). 4
Assisted Reproductive Technology (ART)
- 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
Catastrophic APS
- Aggressive treatment with a combination of anticoagulation, glucocorticoids, and plasma exchange is recommended. 1
- Add intravenous cyclophosphamide if CAPS occurs in the setting of SLE flare (500-1000 mg/m² monthly). 1
Common Pitfalls to Avoid
- Do not rely solely on umbilical-artery Doppler after 34 weeks—incorporate cerebro-placental ratio and abdominal-circumference growth velocity. 1
- Do not withhold anticoagulation based on thrombocytopenia alone unless platelet count is critically low or active bleeding is present. 3, 1
- Do not discontinue aspirin before delivery solely due to anesthesia concerns—aspirin does not typically complicate delivery. 3, 1
- Do not assume normal complement levels exclude an SLE flare—look for declining trends even within the normal range. 1
- Do not use DOACs in triple-positive APS patients—if already on a DOAC, transition to warfarin. 1, 2