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Antiphospholipid syndrome

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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).

  • Coagulation panel: paradoxically prolonged aPTT (caused by lupus anticoagulant, which interfere with in vitro aPTT test)

Antiphospholipid antibodies

  • Lupus anticoagulant (LA): antibodies against certain phospholipids in cellular membranes; detection involves a three-step procedure
    • These antibodies inhibit coagulation and therefore prolong aPTT in vitro, but have a procoagulatory effect in vivo.
    1. Screening for phospholipid-dependent coagulation with either:
      • Paradoxical prolonged aPTT
      • Prolonged dilute Russell viper venom time (dRVVT)
    2. Mixing study: The patient’s plasma is mixed with normal plasma (which contains clotting factors).
      • aPTT or dRVVT normalize: Presence of lupus anticoagulant ruled out; prolonged aPTT may be due to a lack of clotting factors.
      • aPTT or dRVVT remain prolonged: Lupus anticoagulant may be present.
    3. Confirmation of phospholipid dependence: Phospholipid is added.
      • aPTT or dRVVT normalize: Presence of lupus anticoagulants is confirmed.
      • aPTT or dRVVT remain prolonged: Consider a factor deficiency.
  • Anticardiolipin antibodies (IgG and IgM): antibodies against cardiolipin, a phospholipid in cellular membranes
  • Anti-β2-glycoprotein antibodies (IgG and IgM): antibodies directed against the cardiolipin ­binding factor β2­ glycoprotein I that have prothrombotic effects

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.

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