Hematology Question 15 Instructor

Paroxysmal Nocturnal Hemoglobinuria has an incidence of 0.13/100,000. What is the primary defect in this disorder and how does it lead to its primary hematologic abnormalities?

  1. What are the main signs/ symptoms of PNH?
    Symptoms emerge with the increased platelet aggregation and hemolysis with resultant reductions in nitrous oxide:

    • Thrombosis (consider in cases with unusual VTE such as the mesenteric arterial / venous system)
    • Deficiencies in nitric oxide: abdominal pain with smooth muscle bowel wall spasm, erective dysfunction, symptoms of pulmonary hypertension
    • “Red urine” (due to hemoglobinuria)
    • Anemia/ pancytopenia including elevations of markers of hemolysis
  2. What is the leading cause of mortality?
    One-third of patients will die in 5 years, with 40% dying of clot-related disease.
  3. What therapies are efficacious?
    Treatment: Most problems in PNH are due to the unopposed complement against PNH cells. Eculizumab is an approved antibody directed therapy blocking the cleavage of C5 and thereby preventing formation of the membrane attack complex and resultant destruction of blood cells. It is essential patients are vaccinated against N. Meningitides prior to receiving this medication.

Points to consider: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules CD55 and CD59 which protect stem cells aginst complement mediated hemolysis.

It may be acquired with disorders such as aplastic anemia or MDS wherein immune dysregulation and stem cell mutations allow a PNH clone in the bone marrow to proliferate.

Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-1243.

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