Autoimmune disorder with antiphospholipid antibodies causing arterial/venous thrombosis and pregnancy morbidity.
Also known as: APS, antiphospholipid syndrome, Hughes syndrome, lupus anticoagulant, anticardiolipin
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Risk factors
- Systemic lupus erythematosus (30-40% have APL antibodies; ~10-15% develop APS)
- Other autoimmune diseases — Sjögren syndrome, RA, systemic sclerosis
- Infections (transient antibodies) — syphilis, HIV, HCV
- Drug-induced — chlorpromazine, procainamide, hydralazine
- Family history of autoimmune disease
Pathophysiology
Pathogenic autoantibodies, principally anti-β2-glycoprotein-1, bind phospholipid-protein complexes on endothelium, platelets, and trophoblasts. Activation of complement, endothelial cells, and platelets shifts hemostatic balance toward thrombosis. In pregnancy, placental thrombosis and direct trophoblast injury cause miscarriage, IUGR, and preeclampsia.
Clinical presentation
Symptoms
- DVT, PE — most common manifestation
- Arterial thrombosis — stroke (especially in young patients), TIA, MI, limb ischemia
- Recurrent pregnancy loss (≥3 consecutive losses <10 weeks), late fetal loss ≥10 weeks, severe preeclampsia, IUGR
- Livedo reticularis — net-like purple skin discoloration
- Thrombocytopenia (mild-moderate)
- Cardiac valve thickening or vegetations (Libman-Sacks endocarditis)
- Cognitive dysfunction, migraine, transverse myelitis (less common)
Signs / physical exam
- Livedo reticularis or livedo racemosa
- Cutaneous ulcers, digital ischemia
- Cardiac murmur from valve involvement
- Focal neurological deficits
Classic findings
Triad in catastrophic APS: rapidly progressive multi-organ thrombosis (≥3 organs), histologic confirmation of small vessel occlusion, and persistent APL antibodies.
Differential diagnosis
- Hereditary thrombophilias — Family history, venous thrombosis predominant; negative APL antibodies on repeat testing
- Heparin-induced thrombocytopenia — Heparin exposure, platelet drop with thrombosis, positive anti-PF4 antibodies
- TTP / atypical HUS — Microangiopathic hemolytic anemia, schistocytes, low ADAMTS13 (TTP); responds to plasma exchange
- Catastrophic APS (CAPS) — Variant — multi-organ thrombosis within days, mortality >40%
- Malignancy-associated thrombosis — Occult cancer, often pancreatic, lung, GI
- Vasculitis — Constitutional symptoms, multi-system organ involvement, elevated inflammatory markers, characteristic biopsy
Diagnostic workup
Diagnostic criteria
Revised Sapporo (Sydney) criteria — requires ≥1 clinical criterion (vascular thrombosis or pregnancy morbidity) AND ≥1 laboratory criterion (LA, anti-cardiolipin, or anti-β2GP1) on two occasions at least 12 weeks apart. The 2023 ACR/EULAR criteria add weighted domain scoring and emphasize triple positivity.
Labs
- Three core antiphospholipid antibody tests, all measured on TWO occasions ≥12 weeks apart:
- - Lupus anticoagulant (LA) — coagulation-based assay (dRVVT, aPTT-based)
- - Anti-cardiolipin IgG and IgM (medium-high titer)
- - Anti-β2-glycoprotein-1 IgG and IgM
- CBC — assess for thrombocytopenia
- Coagulation studies — prolonged aPTT that does not correct with mixing study suggests lupus anticoagulant
- ANA, anti-dsDNA, complement to evaluate for SLE
- Direct Coombs (may coexist with AIHA)
Imaging
- Duplex US, CTPA, MRI brain as clinically indicated by symptoms
- Echocardiogram to evaluate for Libman-Sacks endocarditis
Treatment
First-line
- Acute thrombosis — therapeutic anticoagulation: unfractionated heparin or LMWH bridge to warfarin (INR 2-3)
- Long-term venous thrombosis — warfarin INR 2-3 indefinitely
- Long-term arterial thrombosis or recurrent venous thrombosis on warfarin — warfarin INR 3-4, or warfarin + low-dose aspirin
- DOACs (rivaroxaban, apixaban) are INFERIOR to warfarin in triple-positive APS — avoid
Obstetric APS (pregnancy)
- Prophylactic LMWH (enoxaparin 40 mg daily) PLUS low-dose aspirin (81 mg)
- Therapeutic LMWH if prior thrombosis
- Continue 6 weeks postpartum
- Avoid warfarin (teratogen 6-12 weeks; safe later); avoid DOACs in pregnancy
Catastrophic APS (CAPS)
- ICU-level care
- Triple therapy: anticoagulation (heparin) + high-dose glucocorticoids + plasma exchange and/or IVIG
- Rituximab or eculizumab for refractory cases
- Treat precipitating triggers (infection, surgery, drug withdrawal)
Asymptomatic antibody carriers
- Low-dose aspirin may be considered in high-risk profiles (triple-positive, SLE)
- Aggressive cardiovascular risk factor modification
- Avoid combined estrogen contraceptives
Second-line / adjunct
- Hydroxychloroquine — adjunctive, especially in SLE-associated APS
- Statins for vascular protection
- Rituximab or eculizumab for refractory/catastrophic disease
Complications
- Recurrent thrombosis despite anticoagulation
- Catastrophic APS (mortality 30-50%)
- Stroke and cumulative cognitive impairment
- Pregnancy loss, severe preeclampsia, HELLP
- Libman-Sacks endocarditis with embolic events
- Diffuse alveolar hemorrhage
- Adrenal hemorrhage and primary adrenal insufficiency
- Chronic kidney disease (APS nephropathy)
PANCE pearls
- Confirm any positive antiphospholipid test ≥12 weeks later — transient positivity occurs with infection.
- Triple-positive APS (LA + anti-cardiolipin + anti-β2GP1) confers highest thrombosis risk and warrants warfarin over DOACs (TRAPS trial).
- A prolonged aPTT that fails to correct on mixing study and corrects with added phospholipid suggests lupus anticoagulant.
- Warfarin INR target 2-3 for venous events; higher (or warfarin + ASA) for arterial events.
- Pregnant patients with APS should receive LMWH + aspirin, not warfarin (teratogen).
- Catastrophic APS is a life-threatening emergency — recognize and start triple therapy immediately.
References
- 2023 ACR/EULAR Criteria — Barbhaiya M et al. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol 2023.
- TRAPS trial — Pengo V et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132:1365-1371.
- Sapporo/Sydney criteria — Miyakis S et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 2006.
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