How is anemia in Paroxysmal Nocturnal Hemoglobinuria (PNH) typically managed?

Presentation of Anemia in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Anemia in PNH presents as a complement-mediated hemolytic anemia characterized by both intravascular and extravascular hemolysis, requiring specific diagnostic testing and treatment with complement inhibitors as the standard of care. 1

Clinical Presentation

PNH anemia typically presents with:

• Hemolytic anemia with evidence of RBC destruction on peripheral smear
• Elevated markers of hemolysis (LDH, indirect bilirubin, reticulocyte count)
• Decreased haptoglobin levels
• Free hemoglobin in plasma
• Hemoglobinuria (especially noticeable in morning urine samples)
• Fatigue and reduced exercise tolerance
• Possible thrombotic complications

Diagnostic Approach

The diagnosis of PNH-related anemia requires:

1. Laboratory evidence of hemolysis:

   • Complete blood count showing anemia
   • Elevated LDH, bilirubin (primarily indirect)
   • Decreased haptoglobin
   • Elevated reticulocyte count
   • Free hemoglobin in plasma

2. Specific PNH testing:

   • Flow cytometry to detect GPI-anchored protein deficiency on blood cells (CD55, CD59)
   • Screening for PNH clone size in granulocytes, monocytes, and red cells 2

3. Exclusion of other causes:

   • Direct antiglobulin test (Coombs test) - typically negative in PNH
   • Evaluation for other hemolytic anemias
   • Bone marrow examination to assess for concurrent bone marrow failure syndromes 2

Management of PNH-Associated Anemia

The management of anemia in PNH has been revolutionized by complement inhibitors:

1. First-line therapy:

   • Terminal complement inhibitors (C5 inhibitors):
     • Eculizumab (IV every 2 weeks)
     • Ravulizumab (IV every 8 weeks)
     • Crovalimab (subcutaneous every 4 weeks) 1

2. For patients with extravascular hemolysis despite C5 inhibition:

   • Upstream complement inhibitors:
     • Pegcetacoplan (C3 inhibitor, subcutaneous twice weekly)
     • Iptacopan (factor B inhibitor, oral twice daily)
     • Danicopan (factor D inhibitor, oral three times daily) - used as add-on to C5 inhibitors 1

3. Supportive care:

   • RBC transfusions for symptomatic anemia or hemoglobin <7-8 g/dL
   • Folic acid supplementation (1 mg daily) 2
   • Iron supplementation if deficient

4. Curative option:

   • Bone marrow transplantation - reserved for patients with suboptimal response to complement inhibitors or those with severe bone marrow failure 3

Clinical Pearls and Pitfalls

• Underdiagnosis: PNH is frequently underdiagnosed, with studies showing only 10.4% of patients with unexplained anemia being tested for PNH despite potential indicators of hemolysis in 24.2% 4

• Extravascular hemolysis: Approximately 30% of patients on C5 inhibitors develop clinically significant extravascular hemolysis due to C3 opsonization of PNH erythrocytes 5, 1

• Breakthrough hemolysis: Can occur during infections or other complement-activating conditions despite complement inhibitor therapy 1

• Thrombosis risk: PNH is associated with a high risk of thrombosis, particularly in unusual sites like hepatic veins (Budd-Chiari syndrome) and portal veins 2

• Monitoring: Patients on complement inhibitors require regular monitoring of hemolysis parameters, hemoglobin levels, and breakthrough hemolysis episodes 1

• Coombs test conversion: Up to 58% of patients on eculizumab become direct Coombs-test positive as a consequence of treatment 5

By recognizing the characteristic presentation of PNH-associated anemia and implementing appropriate diagnostic testing and treatment with complement inhibitors, clinicians can significantly improve outcomes and quality of life for these patients.