antiphospholipid syndrome
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Updated 2026-04-15
Contents
antiphospholipid syndrome
Acquired autoimmune thrombophilia — venous or arterial thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). Requires lifelong Warfarin (not DOACs). Catastrophic APS (CAPS) is a medical emergency with ~30% mortality.
pathophysiology
- Target: autoantibodies against phospholipid-binding proteins (primarily β₂-glycoprotein I) on endothelial cells, monocytes, platelets
- Mechanism: tissue factor upregulation → complement activation → systemic hypercoagulability
- “Two-hit” model: aPL = primed state (first hit); infection, surgery, or pregnancy triggers the event (second hit)
diagnosis
Based on Revised Sapporo (Sydney) Criteria — requires 1 clinical + 1 laboratory criterion.
Sapporo vs. 2023 ACR/EULAR criteria
- Sapporo (clinical use): maximises sensitivity — use these for diagnosis
- 2023 ACR/EULAR (research classification): weighted point system, 99% specific but ~84% sensitive — misses ~16% of patients overall, especially those with isolated IgM positivity or lower titres — do not use for clinical diagnosis
clinical criteria
- Vascular thrombosis: ≥1 episode of arterial, venous, or small vessel thrombosis in any tissue, confirmed by imaging or histopathology
- includes unusual sites — Cerebral Venous Sinus Thrombosis, portal vein thrombosis, Budd-Chiari
- Pregnancy morbidity (any one of):
- ≥1 foetal death at ≥10 weeks (morphologically normal)
- ≥1 premature delivery <34 weeks due to severe pre-eclampsia, eclampsia, or placental insufficiency
- ≥3 spontaneous losses <10 weeks (maternal/chromosomal causes excluded)
laboratory criteria
Must be positive on two occasions ≥12 weeks apart (excludes transient infection-associated positivity).
| Test | Type | Threshold | Notes |
|---|---|---|---|
| Lupus anticoagulant (LA) | Functional clotting assay | Positive per ISTH guidelines | Strongest predictor of thrombosis |
| Anti-cardiolipin (aCL) | ELISA | IgG or IgM >40 GPL/MPL or >99th percentile | Medium-high titre required |
| Anti-β₂-glycoprotein I | ELISA | IgG or IgM >99th percentile | Confirms antigen specificity |
triple positive = highest risk
LA + aCL + anti-β₂GPI all positive → highest-risk profile. Cumulative recurrence ~12% at 1 year, ~26% at 5 years, ~44% at 10 years despite anticoagulation (Pengo et al. 2010). Drives management intensity.
laboratory nuances
- LA paradox: prolongs aPTT in vitro (phospholipid-dependent assay) but is pro-thrombotic in vivo
- LA and anticoagulation: affected by all anticoagulants (Heparin, DOACs, Warfarin) — do not test LA on therapeutic anticoagulation; false results in both directions
- Solid-phase assays (aCL, anti-β₂GPI): ELISA-based, not affected by anticoagulation — can test while on warfarin or DOACs
management
venous thromboembolism
- Warfarin — INR 2.0–3.0, indefinite duration
- APS = persistent risk factor → no finite anticoagulation course
DOACs are contraindicated in high-risk APS
TRAPS (2019) — rivaroxaban vs. warfarin in triple-positive APS: stopped early for increased arterial thrombosis (stroke) and major bleeding with rivaroxaban. Avoid DOACs in triple-positive, arterial, or high-titre APS. Recent meta-analyses confirm increased risk. Some experts may cautiously consider DOACs in selected low-risk single-positive venous APS, but this remains controversial — warfarin is the default.
arterial thrombosis
- Warfarin INR 2.0–3.0 ± Aspirin — EULAR 2019 recommends either INR 2–3 or INR 3–4, based on individual bleeding/thrombosis risk
- Recurrent events despite therapeutic INR → target INR 3.0–4.0 (expert consultation)
- Aggressive CV risk factor control (BP, lipids)
obstetric APS
- Standard: prophylactic LMWH + low-dose Aspirin
- ASA pre-conception; LMWH once pregnancy confirmed
- continue anticoagulation 6 weeks post-partum (high-risk period)
- Refractory: add Hydroxychloroquine or low-dose prednisone
- Warfarin is teratogenic (embryopathy weeks 6–12, dose-dependent — higher risk at >5 mg/day) — contraindicated in first trimester; safe during breastfeeding
catastrophic APS (CAPS)
- ≥3 organs involved in <1 week → “thrombotic storm”
- Mortality: ~30%
- Triggers: infection, surgery, subtherapeutic INR, anticoagulation withdrawal
- Triple therapy:
- IV unfractionated Heparin
- High-dose methylprednisolone
- Plasma exchange (PLEX) or IVIG
- Refractory CAPS: consider Rituximab or eculizumab
what NOT to do
- Do not use DOACs for high-risk APS (triple-positive, arterial, high-titre) — TRAPS evidence
- Do not test lupus anticoagulant while on therapeutic anticoagulation — false results in both directions
- Do not diagnose APS on a single positive aPL — must confirm at ≥12 weeks
- Do not withhold anticoagulation for mild thrombocytopenia — APS-associated thrombocytopenia does not protect against thrombosis
- Do not anticoagulate isolated aPL carriers without clinical events
special populations
isolated aPL carriers (no clinical events)
- No anticoagulation
- Address CV risk factors
- In SLE: Hydroxychloroquine reduces thrombotic risk (primary prevention)
thrombocytopenia
- Common (20–40%), usually mild (70–100 × 10⁹/L)
- Does not protect against thrombosis — continue anticoagulation
unusual-site thrombosis
- APS is a major cause of Budd-Chiari syndrome, portal vein thrombosis, and Cerebral Venous Sinus Thrombosis
- Always test aPL panel in young patients with unusual-site thrombosis
key trials summary
| Trial | Year | Design | Result |
|---|---|---|---|
| TRAPS (2019) | 2019 | RCT, rivaroxaban vs. warfarin, triple-positive APS | Stopped early — rivaroxaban: more arterial events and bleeding |
| Celia et al. (2025) | 2025 | Systematic review & meta-analysis, DOACs vs. VKA in APS | DOACs associated with increased arterial thrombosis vs. warfarin |
| CAPS Registry | 2018 | Registry, n=500 | Triple therapy (AC + steroids + PLEX/IVIG) → best survival in CAPS |