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Antiphospholipid syndrome

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aliasesAPS, Antiphospholipid antibody syndrome

3 min read

Antiphospholipid syndrome (APS) is an autoimmune disease associated with increased risk of thrombosis due to the presence of procoagulatory antibodies.

Etiology

Pathophysiology

  • Core Defect:
    • The autoantibodies are directed against plasma proteins that are bound to anionic phospholipids on cell surfaces (e.g., endothelial cells, platelets, trophoblasts).
    • Despite the name, the primary target is often proteins like β2 glycoprotein I, not the phospholipids themselves.
    • The net effect is a hypercoagulable or prothrombotic state.
  • Key Antibodies & Classic Findings:
    • Lupus Anticoagulant: In vivo procoagulant, but paradoxically causes a prolonged aPTT in vitro that does not correct with a mixing study.
    • Anticardiolipin Antibody: Can cause a false-positive VDRL/RPR test for syphilis.
    • Anti-β2 Glycoprotein I Antibody: Targets the primary antigen.
  • Prothrombotic Mechanisms:
    • Activation of platelets and endothelial cells.
    • Inhibition of natural anticoagulants (e.g., Protein C).
    • Complement activation.
  • Pregnancy Morbidity Mechanism:
    • Thrombosis of placental vessels.
    • Direct inhibition of trophoblast growth and invasion.

Clinical features

APS usually manifests with recurring thrombotic events that may affect any organ.

  • Thrombosis: Recurrent venous (e.g., DVT, PE) or arterial (e.g., stroke, TIA, MI) thrombosis. Stroke in a young patient (<50) should raise suspicion.
  • Obstetric Complications: Recurrent pregnancy loss (especially ≥10 weeks gestation), premature birth due to pre-eclampsia/eclampsia, or placental insufficiency.
    • Caused by thrombosis of placental vessels and possible subsequent placental infarction
  • Other findings: Livedo reticularis (or racemosa), thrombocytopenia, valvular heart disease (Libman-Sacks endocarditis), and neurologic symptoms (migraine, seizures).

Diagnostics

Tip

Thrombosis in APS is typically unprovoked (e.g., unprovoked DVT), recurrent, and/or manifests in unusual sites (e.g., kidneys, liver, retina). It is most commonly seen in younger individuals (< 50 years of age) and in individuals with comorbid autoimmune diseases (e.g., SLE).

  • Clinical Criteria: Sydney consensus requires ≥1 clinical criterion (vascular thrombosis OR obstetric morbidity) + ≥1 lab criterion.
  • Key Labs / Screening:
    • Paradoxical prolonged aPTT: Does not correct upon 1:1 mixing study (indicates presence of an inhibitor/lupus anticoagulant in vitro, despite causing hypercoagulability in vivo).
      • Caused by lupus anticoagulant, which interfere with in vitro aPTT test
    • False-positive VDRL/RPR: Due to cross-reactivity with cardiolipin antigen.
    • Platelet count: Mild thrombocytopenia (consumption).
  • Confirmatory / Gold Standard Antibodies (must test positive on ≥2 occasions at least 12 weeks apart):
    1. Lupus anticoagulant (LA): Tested via dilute Russell viper venom time (dRVVT) or aPTT mixing studies; confirmatory step shows correction with excess phospholipid.
    2. Anti-cardiolipin antibodies (aCL): IgG or IgM (>40 GPL/MPL or >99th percentile).
    3. Anti-β2-glycoprotein I antibodies: IgG or IgM (>99th percentile).
  • Imaging:
    • Duplex US for suspected DVT.
    • CTPA or V/Q scan for suspected PE.
    • MRI/MRA of the brain for suspected CVA/TIA.
    • Transthoracic/Transesophageal Echocardiography (TTE/TEE) to assess for valvular thickening/vegetations.

Tip

Patients with APS can test false positive for syphilis (positive VDRL or RPR) because the antigen used in syphilis tests is cardiolipin. This happens in SLE as well.

Management

  • Asymptomatic / aPL-Positive Only (Primary Prophylaxis):
    • First-line: Low-dose aspirin (LDA) (81 mg/day).
    • If secondary to SLE: Optimize background therapy with Hydroxychloroquine.
  • Definite APS with Thrombosis (Secondary Prevention): c
    • Acute phase: Rapid therapeutic anticoagulation with UFH or LMWH.
    • Long-term: Lifelong Warfarin (Target INR 2.0–3.0).
      • Note: DOACs (e.g., Rivaroxaban) are contraindicated/inferior to warfarin (higher rate of arterial thromboembolic events, especially in triple-positive pts).
    • Recurrent thrombosis despite therapeutic INR: Increase INR target to 3.0–4.0 OR add LDA / switch to LMWH.
  • Obstetric APS:
    • During pregnancy: Low-dose aspirin (LDA) + Prophylactic-dose LMWH (started as soon as pregnancy is confirmed, continued through 6 weeks postpartum).
    • Prior thrombotic event + pregnancy: Switch warfarin to Therapeutic-dose LMWH + LDA (Warfarin is teratogenic).
  • Catastrophic APS (CAPS) (Emergency):
    • First-line: Triple therapy with High-dose IV Methylprednisolone + Therapeutic IV Heparin + Plasmapheresis (PLEX) (or IVIG).
    • Refractory: Eculizumab (anti-C5) or Rituximab.

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