What is the diagnosis and treatment approach for Pivka II (Paroxysmal Nocturnal Hemoglobinuria type II)?

Paroxysmal Nocturnal Hemoglobinuria (PNH): Diagnosis and Treatment

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disorder characterized by complement-mediated hemolysis that requires prompt diagnosis through flow cytometry and treatment with complement inhibitors like eculizumab for optimal outcomes.

Diagnosis

Clinical Presentation

• Intravascular hemolysis (dark-colored urine, especially in morning)
• Fatigue and weakness
• Thrombosis (especially in unusual sites like hepatic veins)
• Abdominal pain
• Dyspnea
• Hemoglobinuria
• Unexplained cytopenias

Diagnostic Workup

1. Flow cytometry of peripheral blood cells (gold standard):

   • Test for CD55 and CD59 deficient clones on erythrocytes, granulocytes, and monocytes 1
   • This is 100% specific for PNH

2. Laboratory tests:

   • Complete blood count (CBC) with evidence of anemia
   • Peripheral blood smear (evidence of hemolysis)
   • Reticulocyte count (typically elevated)
   • LDH (markedly elevated)
   • Haptoglobin (decreased or absent)
   • Direct and indirect bilirubin (elevated)
   • Urinalysis (hemoglobinuria)
   • Renal function tests

3. Additional testing if flow cytometry unavailable:

   • Ham-Dacie test and sucrose test 1

4. Thrombosis evaluation:

   • If thrombosis present, especially in unusual sites like hepatic veins (Budd-Chiari syndrome) or portal vein, PNH should be considered 1

Differential Diagnosis

• Autoimmune hemolytic anemia
• Other hemolytic anemias
• Myelodysplastic syndromes
• Aplastic anemia (often coexists with PNH)
• Other causes of hemoglobinuria

Treatment

First-line Therapy

• Complement inhibitor therapy:
  • Eculizumab is the preferred treatment for patients with symptomatic PNH 1
  • Long-term treatment with eculizumab is indicated in PNH patients with thrombosis 1

Anticoagulation

• For PNH patients with thrombosis:
  • Initiate anticoagulation with vitamin K antagonists (VKA)
  • Continue anticoagulation indefinitely 1
  • Consider eculizumab in addition to anticoagulation

Supportive Care

• Red blood cell transfusions for symptomatic anemia
• Folic acid supplementation (1 mg daily) 1
• Iron supplementation if deficient
• Avoid iron overload in transfusion-dependent patients

Management of Complications

1. Thrombosis:

   • Immediate anticoagulation
   • Consider thrombolysis for acute life-threatening thrombosis
   • Evaluate for Budd-Chiari syndrome or portal vein thrombosis

2. Renal insufficiency:

   • Monitor renal function
   • Maintain adequate hydration
   • Consider eculizumab to prevent further renal damage

3. Bone marrow failure:

   • Consider immunosuppressive therapy or hematopoietic stem cell transplantation

Definitive Treatment

• Allogeneic hematopoietic stem cell transplantation:
  • Consider in young patients with severe disease
  • Especially indicated in patients with concurrent aplastic anemia
  • High-risk procedure with significant morbidity and mortality

Monitoring

• Regular CBC monitoring
• LDH levels to assess hemolysis
• Renal function tests
• Screening for thrombotic events
• Flow cytometry to assess PNH clone size periodically

Important Considerations

• PNH is often misdiagnosed or diagnosis is delayed due to its rarity and variable presentation
• PNH should be considered in any patient with unexplained hemolysis, cytopenias, or thrombosis in unusual sites
• Flow cytometry is the definitive diagnostic test and should be performed at specialized centers
• Early diagnosis and treatment significantly improve outcomes and quality of life
• Thrombosis is the leading cause of mortality in PNH and requires aggressive management

Common Pitfalls

• Failure to consider PNH in patients with unexplained hemolysis or thrombosis
• Relying on urinalysis alone (hemoglobinuria may be intermittent)
• Not testing for PNH in patients with aplastic anemia or unexplained cytopenias
• Delaying treatment in symptomatic patients
• Inadequate anticoagulation in patients with thrombosis