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Antiphospholipid Antibody Syndrome (APS)

Basics

  • Autoantibody-mediated thrombophilic disorder.
  • Recurrent arterial or venous thrombosis and/or fetal loss.
  • Persistent antiphospholipid antibodies (LAC, aCL, anti-β2-GPI).
  • Types:
  • Primary (no underlying condition).
  • Secondary (commonly with SLE).
  • Catastrophic APS (CAPS): thrombotic microangiopathy with multiorgan failure; high mortality.

Epidemiology

  • Incidence: ~5 new cases per 100,000/year.
  • Female > male.
  • APA prevalence: 1-5% general population; ~40% in SLE.
  • Increased thrombosis risk with triple antibody positivity.

Etiology & Pathophysiology

  • Anti-β2-GP1 antibodies central to pathogenesis.
  • Mechanisms:
  • Endothelial dysfunction: decreased prostacyclin, loss of annexin V shield.
  • Platelet activation.
  • Inhibition of natural anticoagulant pathways (e.g., protein C).
  • Complement activation.
  • Pregnancy complications from abnormal placentation and thrombosis.
  • Environmental "second hit" often triggers clinical disease.

Risk Factors

  • Age >55 (males), >65 (females).
  • Cardiovascular risks: HTN, hyperlipidemia, diabetes, obesity, smoking, combined OCP use.
  • Autoimmune diseases (SLE most common), malignancy, infections, drugs.

Commonly Associated Conditions

  • SLE, scleroderma, Sjögren syndrome, dermatomyositis, rheumatoid arthritis.
  • HELLP syndrome.
  • Sneddon syndrome variant (livedo reticularis, HTN, stroke).

Diagnosis

Clinical Criteria (Sapporo/Sydney 2006)

  • Vascular thrombosis (arterial, venous, or small vessel) confirmed by imaging/histopathology.
  • Pregnancy morbidity:
  • ≥3 consecutive spontaneous abortions <10 weeks.
  • ≥1 unexplained fetal death ≥10 weeks.
  • ≥1 premature birth ≤34 weeks due to severe preeclampsia/eclampsia/placental insufficiency.

Laboratory Criteria (confirmed ≥12 weeks apart)

  • Lupus anticoagulant (LAC) positive.
  • Moderate/high anticardiolipin IgG/IgM antibodies (>40 GPL/MPL or >99th percentile).
  • Anti-β2-GP1 IgG/IgM antibodies (>99th percentile).

History & Physical Exam

  • History: venous/arterial thrombosis, recurrent fetal loss, autoimmune diseases.
  • Exam: venous thrombosis signs, livedo reticularis, palpable purpura, thrombophlebitis, cardiac murmurs, neurologic deficits.

Differential Diagnosis

  • Inherited thrombophilias: protein C/S deficiency, antithrombin III deficiency, factor V Leiden.
  • Acquired: malignancies, hyperviscosity syndromes, nephrotic syndrome.
  • Embolic diseases: atrial fibrillation, endocarditis, cholesterol emboli.
  • DIC, PNH, heparin-induced thrombocytopenia, Behçet syndrome, thrombotic microangiopathies.

Diagnostic Tests

  • CBC, PT/INR, aPTT.
  • LAC assay: combination of aPTT, dRVVT, kaolin clotting with confirmatory tests.
  • ELISA for anticardiolipin and anti-β2-GP1 antibodies.
  • Repeat testing at 12 weeks for persistence.
  • Imaging based on thrombosis location.
  • Biopsy as needed for vasculitis differentiation.

Treatment

Primary Thromboprophylaxis

  • Controversial in asymptomatic patients with positive APAs.
  • Low-dose aspirin or heparin reserved for high-risk patients.

Secondary Thromboprophylaxis

  • Lifelong anticoagulation for symptomatic patients.
  • Warfarin with INR 2-3 for venous thrombosis.
  • INR 3-4 for arterial thrombosis or recurrent events.
  • LMWH/fondaparinux alternatives.
  • DOACs not routinely recommended; may increase recurrent thrombosis risk.

Adjuncts

  • Rituximab, hydroxychloroquine, statins in refractory cases.
  • Vitamin D supplementation.

Catastrophic APS (CAPS)

  • Anticoagulants, high-dose steroids, IVIG or plasma exchange.
  • Improved survival with aggressive therapy.

Pregnancy

  • Low-dose aspirin ± prophylactic heparin for women without thrombosis.
  • Therapeutic anticoagulation for women with history of thrombosis.
  • Warfarin contraindicated.
  • Maternal-fetal medicine consultation advised for refractory cases.

Ongoing Care

  • Monitor INR, medication compliance.
  • Avoid oral hormonal contraceptives.
  • Manage cardiovascular risk factors.

Prognosis

  • Worse with pulmonary hypertension, neurologic involvement, myocardial ischemia, nephropathy, CAPS.
  • 30% risk of recurrent thrombosis without anticoagulation.
  • Pregnancy complications increase morbidity/mortality.

Clinical Pearls

  • APS requires both clinical and lab criteria confirmed ≥12 weeks apart.
  • Lifelong anticoagulation is usually necessary.
  • CAPS is a medical emergency with high mortality.
  • APS is multisystem with high morbidity from thrombotic complications.