What are the primary features of Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Primary Features of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) is primarily characterized by the triad of intravascular hemolysis, thrombosis (especially in unusual sites), and bone marrow failure of variable degrees, resulting from a rare acquired clonal hematopoietic stem cell disorder. 1

Pathophysiology

PNH is caused by an acquired somatic mutation in the PIGA gene in hematopoietic stem cells, leading to:

• Deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins on cell surfaces
• Reduced or absent expression of complement regulatory proteins (particularly CD55 and CD59)
• Increased susceptibility of blood cells to complement-mediated damage 2

Key Clinical Manifestations

1. Hemolytic Anemia

• Intravascular hemolysis (primary feature)
• Hemoglobinuria (dark urine, especially noticeable in morning)
• Chronic anemia with potential exacerbations
• Fatigue and weakness
• Extravascular hemolysis (may persist even with C5 inhibitor therapy) 3

2. Thrombotic Complications

• Affects up to 40% of PNH patients
• Venous thrombosis predominates, particularly in unusual sites:
  • Hepatic veins (Budd-Chiari syndrome in 9-19% of cases)
  • Portal vein thrombosis
  • Mesenteric veins
  • Cerebral veins 4, 1
• Increased risk with PNH clone size >60% of granulocytes 4
• Major cause of mortality in untreated patients 1

3. Bone Marrow Dysfunction

• Variable degrees of bone marrow failure
• Frequently associated with:
  • Aplastic anemia
  • Myelodysplastic syndrome 5
• Manifestations include:
  • Neutropenia
  • Thrombocytopenia
  • Pancytopenia 5

Diagnostic Features

• Flow cytometry to detect absence of GPI-anchored proteins on blood cells
• Testing for PNH clone size in granulocytes (>60% associated with higher thrombosis risk) 4
• Elevated lactate dehydrogenase (LDH) levels due to hemolysis
• Hemoglobinuria and hemosiderinuria
• Reticulocytosis
• Low haptoglobin levels
• Bone marrow examination to assess for associated conditions 4

Clinical Course and Prognosis

• Highly variable clinical course
• Prior to complement inhibitor therapy, mortality was approximately 50%
• Thrombotic complications were the main cause of death
• With C5 inhibitor therapy (eculizumab, ravulizumab), survival approaches that of healthy controls 2
• Quality of life significantly improved with modern therapies 2, 3

Treatment Considerations

• C5 inhibitors (eculizumab, ravulizumab) are the mainstay of treatment
• Effectively control intravascular hemolysis and reduce thrombosis risk
• Approximately 30% of patients on C5 inhibitors develop clinically significant extravascular hemolysis 2
• Newer therapies targeting proximal complement pathways (pegcetacoplan, iptacopan) address both intravascular and extravascular hemolysis 2
• Long-term anticoagulation may be needed for patients with thrombotic events 1

Important Clinical Pitfalls

1. PNH may be misdiagnosed as other hemolytic anemias or myelodysplastic syndromes
2. Thrombosis may be the first clinical manifestation of PNH, requiring screening in cases of unusual site thrombosis
3. Testing for PNH should be routinely performed in all Budd-Chiari syndrome patients and considered in portal vein thrombosis 4
4. Patients with bone marrow failure syndromes should be screened for PNH
5. Breakthrough hemolysis can occur with complement inhibitor therapy during infections or other complement-activating conditions 2

Understanding these features is crucial for early diagnosis and appropriate management to prevent life-threatening complications and improve quality of life in patients with PNH.