Updated: 1/2/2017

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
  • 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
  • May cause
    • aplastic anemia
    • myelodysplasia
    • acute leukemia
  • Diagnosis often made during pregnancy
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
Evaluation
  • Flow cytometry – most accurate test
    • CD55/59-negative RBCs
  • Labs
    • anemia
    • thrombocytopenia
    • leukopenia
Differential Diagnosis
  • Aplastic anemia
  • Myelodysplasia
Treatment
  • Best initial therapy – eculizumab
    • 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
Prognosis, Prevention, and Complications
  • Prognosis
    • improved with use of eculizumab
  • Complications
    • renal insufficiency
    • thromboembolism
    • 5% develop myelodysplasia
    • 2.5% develop acute leukemias
 

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