Hemoglobinuria, Paroxysmal Nocturnal

Key Features

• Acquired clonal hematopoietic stem cell disorder causing abnormal sensitivity of red blood cell (RBC) membrane to lysis by complement and therefore hemolysis

• Defect involves deficient proteins CD55 and CD59, which permits unregulated formation of the complement membrane attack complex on RBC membranes and thus intravascular hemolysis

• Suspect diagnosis in confusing cases of hemolytic anemia or pancytopenia

Clinical Findings

• Hemoglobinuria (reddish brown urine), particularly in first morning urine

• Anemia

• Increased susceptibility to thrombosis, especially of mesenteric and hepatic veins

• May appear de novo or arise in the setting of aplastic anemia or myelodysplasia with possible progression to acute myeloid leukemia

Diagnosis

• Flow cytometry best screening test to demonstrate absence of CD59 and CD55 on RBCs

• FLAER assay (fluorescein-labeled proaerolysin) by flow cytometry is even more sensitive

• Anemia of variable severity

• Reticulocytosis may or may not be present

• Urine hemosiderin test may indicate episodic intravascular hemolysis

• Serum lactate dehydrogenase characteristically elevated

• Iron deficiency common because of chronic iron loss from hemoglobinuria

• WBC and platelet count may be low

• Bone marrow morphology variable; may show generalized hypoplasia or erythroid hyperplasia

• Bone marrow karyotype may be either normal or demonstrate a clonal abnormality

Treatment

• Mild disease does not require intervention

• Allogeneic hematopoietic stem cell transplantation has been used in severe cases and in those occurring in setting of myelodysplasia or previous aplastic anemia

• Eculizumab

  • A monoclonal antibody complement inhibitor

  • Doses 1–4: 600 mg intravenously weekly for the first 4 weeks, followed by

  • Dose 5: 900 mg intravenously 1 week later, then

  • Doses 6 onward: 900 mg intravenously every 2 weeks thereafter

  • Warranted in patients with severe hemolysis (usually requiring RBC transfusions) or thrombosis

  • Reduces hemolysis, transfusion requirements, fatigue, and thrombosis risk

  • Improves quality of life

  • Expensive

  • Increases the risk of Neisseria meningitidis infections; patients receiving the antibody should undergo meningococcal vaccination and take oral penicillin (or equivalent) meningococcal prophylaxis

• Ravulizumab-cwvz

  • A longer-acting version of eculizumab

  • Dose is weight-based:

    • 20–29 kg: Administered as 2100 mg intravenously every 8 weeks, starting week 3; 900 mg intravenously × 1 on week 1, beginning 2 weeks after last eculizumab maintenance dose or 1 week after last eculizumab induction dose if switching from eculizumab. Administered intravenously once every 8 weeks

    • 30–39 kg: Administered as 2700 mg intravenously every 8 weeks, starting week 3; 1200 mg intravenously × 1 on week 1, beginning 2 weeks after last eculizumab maintenance dose or 1 week after last eculizumab induction dose if switching from eculizumab. Administered intravenously once every 8 weeks

    • 60–99 kg: Administered as 3300 mg intravenously every 8 weeks, starting week 3; 2700 mg intravenously × 1 on week 1, beginning 2 weeks after last eculizumab maintenance dose or 1 week after last eculizumab induction dose if switching from eculizumab. Administered intravenously once every ...