An acquired genetic defect of the hematopoietic stem cell characterized by a triad of hemolytic anemia, pancytopenia, and thrombosis

Epidemiology

Etiology

Pathophysiology

• Physiologically, a membrane-bound glycosylphosphatidylinositol (GPI) anchor protects RBCs against complement-mediated hemolysis.
• Acquired mutation on the PIGA gene located on the X chromosome → GPI anchor loses its protective effect → RBC destruction by complement and reticuloendothelial system → intravascular and extravascular hemolysis
• The GPI anchor proteins involved in PNH are:
  • CD55/DAF (Decay-accelerating factor)
  • CD59/MIRL (Membrane inhibitor of reactive lysis)
• PNH can also occur in patients with aplastic anemia and MDS.
• Autoimmunity to HSCs, causing bone marrow failure → pancytopenia

Clinical features

• Pallor, excessive fatigue, weakness
• Intermittent jaundice
• Episodes of hemoglobinuria causing pink/red/dark urine which usually occurs in the morning due to the concentration of urine overnight.
• Vasoconstriction
  • The scavenging of nitric oxide by free Hb results in smooth muscle contraction.
  • Headache, pulmonary hypertension
  • Abdominal pain, dysphagia, erectile dysfunction
• Venous thrombosis in unusual locations (e.g., hepatic, cerebral, and/or abdominal veins)
  • Hemolysis generates free Hb, which scavenges serum nitric oxide (a vasodilator), causing vasoconstriction.
  • Free Hb also promotes oxidative stress, which activates the endothelium of blood vessels, inducing platelet aggregation.
• Increased risk of infections (in case of pancytopenia)

Diagnostics

• CBC: anemia, thrombocytopenia, and/or pancytopenia ; usually ↑ reticulocytes
• Hemolysis workup: ↓ haptoglobin
• Direct Coombs test: negative
  • complement-mediated RBC destruction
• Flow cytometry of peripheral blood (confirmatory test for PNH): can show deficiency of GPI-linked proteins on the surface of RBCs and WBCs (e.g., CD55, CD59)

Treatment