17 Antiphospholipid Syndrome
- APS dx: 1 clinical + 1 lab criterion, persistent ≥12 wk
- Clinical: thrombosis OR pregnancy morbidity
- Lab: LAC, aCL, anti-β2GPI
- Manifestations: arterial/venous/microvascular thrombosis, pregnancy loss, thrombocytopenia, livedo, hemolytic anemia
- Lab criteria: moderate-high titer aCL/β2GPI IgG/IgM (>40 units) OR LAC positive x2 occasions
- LAC testing: 3-step clot-based assay; avoid acute phase, heparin, anticoagulation
- Triple+ (all 3 abs): highest recurrence risk
- Tx: VKA INR 2-3 (NOT DOACs); confirm w/ chromogenic factor X if LAC+
- CAPS: multi-organ thrombosis <1 wk; triple therapy (AC + steroids + PLEX/IVIg)
- Obstetric APS: LMWH + low-dose aspirin for hx ≥3 losses or 1 late loss/preterm
17.1 Definition & Pathophysiology
APS: acquired systemic prothrombotic disease w/ persistent APLAs - Arterial/venous/microvascular thrombosis OR pregnancy complications - Nonthrombotic: thrombocytopenia, microvascular disease, cardiac valve disease
APLAs: autoantibodies against phospholipid-binding proteins - aCL IgG/IgM - Anti-β2GPI IgG/IgM - LAC: interferes w/ in vitro clotting
Pathogenesis: endothelial activation, complement cascade defects, impaired thrombin regulation
17.2 Diagnosis of APS
Requires BOTH: 1. ≥1 Clinical criterion (thrombosis OR pregnancy morbidity) 2. ≥1 Lab criterion (persistent ≥12 wk apart)
Lab Criteria (≥1 required): - aCL/β2GPI IgG/IgM >40 units OR >99th percentile on 2 occasions ≥12 wk - LAC positive on 2 occasions ≥12 wk
Clinical Criteria (≥1 required): - Thrombosis: ≥1 objectively documented arterial/venous/microvascular event - Pregnancy morbidity: ≥3 unexplained losses <10 wk OR ≥1 loss ≥10 wk OR prematurity <34 wk
17.3 Epidemiology
APLA prevalence: - ~5% general population, ~30% SLE patients - 6% women w/ pregnancy loss, 10% VTE, 11% MI, 17% young stroke
APS types: - Primary: isolated disease - Secondary: a/w SLE, malignancy, drugs
Clinical heterogeneity: phenotypic variation large; prognosis not generalizable
17.4 Laboratory Testing
Persistence requirement: ≥2 positive tests ≥12 wk apart to exclude transient APLA
| Criteria | Revised Sapporo 2006 | ACR/EULAR 2023 |
|---|---|---|
| Diagnostic requirement | ≥1 clinical + ≥1 lab | ≥3 points (clinical + lab domains) |
| LAC | ✓ | 1 pt (single); 3 pts (persistent) |
| aCL or β2GPI IgG 40-79 | ✓ | 4 pts |
| Both aCL & β2GPI IgG ≥80 | ✓ | 7 pts |
| aCL or β2GPI IgM ≥40 | ✓ | 1 pt |
| Timeline | Within 5 y | Within 3 y |
aCL & anti-β2GPI (ELISA/chemiluminescence): - Measured in IgG/IgM - >40 units = moderate-high titer - ≥80 units weighted more heavily (ACR/EULAR) - Poor interlaboratory standardization
LAC Testing (phospholipid-dependent clot assays): - Use 2 parallel tests (aPTT-based + Russell viper venom) - 3-step confirmation: 1. Prolonged LAC-sensitive assay 2. Incomplete correction w/ 1:1 normal plasma mix 3. Shortened time w/ added phospholipid - Avoid in: acute phase reactants, heparin, DOACs, factor VIII inhibitors - Heparin: false-negative (use anti-Xa level) - Anticoagulation: interferes w/ assay
Markedly prolonged PT in LAC+: check factor II activity (r/o acquired deficiency, bleeding risk)
Other APLAs: anti-PS/prothrombin not in criteria; unclear association w/ thrombosis
17.5 Clinical Features & Manifestations
Thrombosis (most common): - Arterial: stroke, MI, TIA - Venous: DVT, PE (any location) - Microvascular: thrombotic microangiopathy
Nonthrombotic manifestations: - Thrombocytopenia, hemolytic anemia - Livedo reticularis, skin nodules - Cognitive impairment, white matter changes - Cardiac valve thickening/vegetations
Triple positivity (aCL + β2GPI + LAC): ↑↑ recurrence risk
INR Monitoring w/ LAC: - LAC interferes w/ INR; confirm accuracy w/ chromogenic factor X - Chromogenic factor X INR 2.0-3.0 ≈ factor activity 20%-40% - Alt: measure factor II, VII, X activities (may be affected by LAC)
Chromogenic factor X assay essential for reliable VKA monitoring in LAC+ patients.
17.6 Management
Thrombotic APS: - 1st line: VKA (warfarin) INR 2-3, long-term - Unprovoked thrombosis & arterial events: indefinite anticoagulation - Confirm INR w/ chromogenic factor X if LAC+ - DOACs: limited evidence; NOT recommended for APS thrombosis
Obstetric APS (no prior thrombosis): - LMWH + low-dose aspirin for pregnancy - Indications: ≥3 early losses (<10 wk) OR ≥1 late loss/preterm (<34 wk)
Adjunctive therapies: - Hydroxychloroquine: consider for refractory thrombosis (limited data) - Rituximab: thrombocytopenia, hemolytic anemia, CAPS
Primary prevention: - No data for APL+ asymptomatic patients - Low-dose aspirin if ↑ CVD risk (discuss risks/benefits)
17.7 Catastrophic APS (CAPS)
Definition: multi-organ thrombosis w/ high mortality >50% - Rare (<1% APS), life-threatening, requires rapid recognition
Diagnostic criteria: 1. ≥3 organs/tissues involved (micro or macrovascular) 2. Manifestations within ≤1 wk 3. Thrombosis confirmed by imaging 4. APL positivity documented
Triggers: infection, trauma, anticoagulation withdrawal, malignancy
Treatment: - Triple therapy: AC + corticosteroids + PLEX/IVIg - Treat underlying trigger - Consider anticomplement therapy (emerging)
17.8 APS in Pregnancy
Mechanisms: decidual inflammation, complement activation, ↓ endothelial NO, spiral artery remodeling defects
Obstetric manifestations: recurrent fetal loss, oligohydramnios, placental insufficiency, preterm birth
Treatment (LMWH + aspirin superior to aspirin alone): - ≥3 early losses (<10 wk) OR ≥1 late loss (≥10 wk)/preterm (<34 wk): combination therapy - Prior thrombosis: therapeutic-dose LMWH + aspirin - Placental dysfunction: guideline variation exists
17.9 Bibliography
Andreoli L, Chighizola CB, Banzato A, et al. Diagnosis and management of antiphospholipid syndrome. N Engl J Med. 2018;379(13):1290-1303.
Barbhaiya M, Zuily S, Naden R, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Annals Rheum Dis. 2023;82(1):687-1702.
Garcia DL, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;379(13):1290.