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Updated: Dec 16 2021

Paroxysmal Nocturnal Hemoglobinuria (PNH)

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  • Snapshot
    • A 29-year-old woman presents to the emergency room with a high fever and cough. She has been feeling fatigued for a year prior to presentation. Chest radiography reveals a lower lobe pneumonia. Labs reveal Hb 6.7 g/dL, leukocyte count of 5,000/mm3, platelets of 100,000/mm3,high reticulocyte count, and high LDH. Coombs test was negative. Concerned with the apparent intravascular hemolysis, a bone marrow biopsy showed hypercellularity and normal cytogenetics. Flow cytometry was positive for CD55/CD59-negative RBCs.
  • Introduction
    • Clonal stem cell defect from mutation in hematopoietic stem cell
    • May cause
      • aplastic anemia
      • myelodysplasia
      • acute leukemia
  • ETIOLOGY
    • Pathogenesis
      • mutation in PIGA gene
      • defect in glycosylphosphatidylinositol (GPI) anchors CD55 (decay-accelerating factor) and CD59 on RBC membrane
        • these protect RBC from complement
        • DAF inhibits C3 convertase
      • complement-mediated destruction of RBCs
      • activation of platelets and WBCs
    • "PNH Thrombosis"
      • Pancytopenia
      • Nocturnal build up of dark urine
      • Coombs negative Hemolytic anemia (complement-mediated)
      • venous Thrombosis
        • from pro-coagulant and pro-inflammatory state formed by complement activation
  • Presentation
    • Symptoms/physical exam
      • episodic dark urine with first urine of the day
        • caused by hemoglobin
      • chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria
      • acute hemolytic episodes from activators of complement
        • surgery
        • infection
        • stress
        • alcohol
      • thrombocytopenia: mucosal bleeding, petechiae, and ecchymoses
      • leukemia: infections
      • thrombosis
        • abdominal pain, fever, and rectal bleeding (mesenteric vein thrombosis)
        • headache, vomiting, and seizures (cerebral venous sinous thrombosis)
        • fever, jaundice, hepatomegaly (Budd-Chiari syndrome)
      • renal impairment
  • STUDIES
    • Flow cytometry – most accurate test
      • CD55/59-negative RBCs
    • Labs
      • anemia
      • thrombocytopenia
      • leukopenia
  • Differential Diagnosis
    • Aplastic anemia
    • Myelodysplasia
  • DIAGNOSIS
    • Diagnosis often made during pregnancy
  • Treatment
    • Best initial therapy – eculizumab (or ravulizumab)
      • inactivates C5 in complement pathway
      • decreases red cell destruction
      • complement inhibitor
      • must vaccinate all against Neisseria due to increased risk
    • Best curative therapy – allogeneic bone marrow transplant
    • Supportive therapy
      • folic acid
      • transfusions as needed
  • Complications
    • Renal insufficiency
    • Thromboembolism
    • 5% develop myelodysplasia
    • 2.5% develop acute leukemias
  • Prognosis
    • Improved with use of eculizumab
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