Paroxysmal nocturnal hemoglobinuria

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Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia caused by an acquired defect of the phosphatidylinositol glycan anchor (PIGA) gene, which leads to dysfunction of a red cell membrane protein (glycosylphosphatidylinositol) that is normally responsible for protecting RBCs from complement-mediated destruction. PNH can present with clinical features of hemolysis (particularly signs of anemia and episodic hemoglobinuria), systemic vasoconstriction, venous thromboemboli, and pancytopenia. It can also occur in patients with aplastic anemia or myelodysplastic syndrome. Diagnostics typically reveal laboratory signs of hemolysis with a negative direct Coombs test (DAT), and PNH can be confirmed using flow cytometry of peripheral blood. Management ranges from watchful waiting and supportive care to targeted anti-C5 antibody therapy (e.g., eculizumab, ravulizumab) for patients with significant clinical manifestations. Notable complications include Budd-Chiari syndrome, infections, and acute leukemia.

An acquired genetic defect of the hematopoietic stem cell characterized by a triad of hemolytic anemia, pancytopenia, and thrombosis ^[2]

• Median age of onset: approx. 35–40 years.
• ♀ = ♂

Epidemiological data refers to the US, unless otherwise specified.

• 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 ^[5]
• 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. ^[6][7][8]

• 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. ^[2][9]
• Vasoconstriction ^[9]
  • Headache, pulmonary hypertension
  • Abdominal pain, dysphagia, erectile dysfunction
• Venous thrombosis in unusual locations (e.g., hepatic, cerebral, and/or abdominal veins) ^[4]
• Increased risk of infections (in case of pancytopenia)

• CBC: anemia, thrombocytopenia, and/or pancytopenia ; usually ↑ reticulocytes ^[5][10]
• Hemolysis workup: ↓ haptoglobin, hemosiderinuria, hemoglobinuria ^[9]
• Direct Coombs test: negative ^[5]
• 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) ^[11]
  • Indications ^[11][12]
    • Thrombosis with unusual features
    • Unexplained Coombs-negative hemolysis and/or hemoglobinuria
    • Consider performing as part of the workup for unexplained cytopenias, aplastic anemia, and myelodysplastic syndrome (MDS).
• Bone marrow biopsy: not required for the diagnosis of PNH, but indicated in patients with significant pancytopenia
• Additional studies: to assess for complications, for example:
  • Renal function tests
  • Liver chemistries and ultrasound abdomen with duplex scanning

CATCH PNH by testing patients with any of the following: Cytopenias, Aplastic anemia/MDS, Thrombosis, Coombs-negative hemolysis, and/or Hemoglobinuria. ^[11]

Typical biochemical findings in hemolysis include ↓ haptoglobin, ↑ LDH concentration, ↑ indirect bilirubin concentration, peripheral blood smear abnormalities (e.g., ↑ reticulocytes, schistocytes, spherocytes, polychromasia), and urinalysis abnormalities (e.g., hemoglobinuria, hemosiderinuria, and urobilinogen).

References: ^[10][12]

Approach ^[5][10][11]

• Patients with mild or no clinical manifestations: watchful waiting with close surveillance
• Patients with significant clinical manifestations: Start targeted therapy.
• Provide supportive care for all patients.

Targeted therapy ^[5][10][11]

• Indications include severe anemia, thrombosis, severe fatigue, pain crises, and end-organ damage
• First-line treatment: complement inhibition with an anti-C5 antibody (e.g., eculizumab , ravulizumab)
• Second-line treatment: allogeneic hematopoietic stem cell transplantation
  • It is a curative treatment but is associated with increased mortality due to complications. ^[9]
  • Consider in severe aplastic anemia or clonal evolution (e.g., MDS, leukemia).

Supportive care ^{[5][9][10][11]}

• Anemia
  • Consider RBC transfusion in symptomatic or severe anemia (e.g., Hb < 7.0 mg/dL).
  • Consider iron and folic acid supplementation.
• Thrombosis
  • Consider VTE prophylaxis for patients who have active hemolysis or a history of VTE and have not been treated with eculizumab.
  • Avoid medications that increase the risk of thrombosis (e.g., oral contraceptives).
  • Start therapeutic anticoagulation without delay for any venous thromboembolic event (e.g., deep vein thrombosis, pulmonary embolism).
  • Decisions regarding therapeutic anticoagulation for arterial thromboembolic events should be made in consultation with a specialist.
• Neisseria meningitidis infection
  • High risk of infection in patients receiving eculizumab
  • Consider vaccination and antibiotic prophylaxis (see “Prevention” in “Meningitis”).

Consider eculizumab in patients with PNH and thromboembolism, as it is thought to prevent thrombus propagation and protect patients from further thromboembolic events. ^[10]

• Vasoconstriction and thrombotic emboli leading to thrombotic complications, e.g., infarction, Budd-Chiari syndrome ^[13]
• Development of acute leukemia
• Renal failure
• Smooth muscle dystonia
• Pulmonary hypertension

References: ^[10]

We list the most important complications. The selection is not exhaustive.