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

Etiology

• Primary
  • Idiopathic
• Secondary
  • Systemic lupus erythematosus (most common cause of secondary APS)
  • Rheumatoid arthritis
  • Neoplasms

Pathophysiology

• Formation of procoagulatory antiphospholipid antibodies
  • In most cases, the antibodies are formed secondary to autoimmune diseases or infections (see “Etiology” above).
  • Antibodies form complexes with anticoagulant proteins, thereby inactivating them (e.g., protein C, protein S, antithrombin III).
  • Antibodies activate platelets and vascular endothelium, leading to increased binding of platelets
• Induction of a hypercoagulable state → ↑ risk of thrombosis and embolism

Clinical features

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

• Venous
  • Deep vein thrombosis
    • There is diffuse edema and erythema of the right leg and foot. The diameter of the right calf is visibly greater than that of the left.
  • Pulmonary embolism
  • Livedo reticularis
    • Blood clots in capillaries lead to swelling of venules, resulting in a purplish, net-like discoloration of the skin.
  • Ulceration
• Arterial
  • Stroke, transient ischemic attacks
  • Occlusion of organ arteries (e.g., myocardial infarction)
  • Occlusion of distal extremity arteries (ischemia and gangrene)
• Capillaries: splinter hemorrhages
• Pregnancy-related: recurrent miscarriages and premature births
  • Caused by thrombosis of placental vessels and possible subsequent placental infarction

Diagnostics

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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: prolonged aPTT (caused by lupus anticoagulant)

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.