What are the symptoms and treatment options for Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Symptoms and Treatment Options for Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis leading to symptoms including fatigue, shortness of breath, hemoglobinuria, abdominal pain, and thrombotic events, and is treated primarily with complement inhibitors such as eculizumab or ravulizumab to reduce hemolysis and prevent complications.

Clinical Presentation and Symptoms

Common Symptoms

• Fatigue and weakness are among the most frequent presenting symptoms due to anemia and impaired oxygen transport 1
• Shortness of breath (dyspnea), especially during exertion, is common and may progress to dyspnea at rest as the disease worsens 2
• Hemoglobinuria (dark or red-colored urine) due to intravascular hemolysis, often with nocturnal exacerbations 3
• Abdominal pain, which can be severe and related to smooth muscle dystonias or thrombotic events 2

Thrombotic Manifestations

• Venous thrombosis is a major complication and leading cause of mortality in PNH 3
• Intra-abdominal thrombosis (including hepatic, portal, and mesenteric veins) is particularly common 4
• Renal vein thrombosis can occur and lead to renal dysfunction 4
• Thrombosis occurs secondary to nitric oxide deficiency, release of procoagulants, increased tissue factor, and reduced fibrinolysis 4

Hematologic Manifestations

• Hemolytic anemia with associated symptoms (pallor, fatigue, reduced exercise tolerance) 1
• Pancytopenia may be present, especially in patients with concurrent bone marrow failure 3
• Neutropenia and thrombocytopenia can lead to increased infection risk and bleeding tendencies 3

Other Clinical Manifestations

• Smooth muscle dystonias causing esophageal spasms, erectile dysfunction, or abdominal pain 2
• Pulmonary hypertension as a complication of chronic hemolysis 5
• Renal dysfunction or failure from hemoglobinuria and/or thrombosis 5
• Chest pain that may mimic angina 2

Diagnosis

Laboratory Testing

• Flow cytometry is the primary diagnostic tool to detect deficiency of GPI-anchored proteins (CD55 and CD59) on blood cells 4
• Fluorescein-labeled proaerolysin variant (FLAER) assay has advantages over CD55/CD59 testing for diagnosis 4
• Complete blood count typically shows anemia with elevated reticulocyte count 1
• Elevated lactate dehydrogenase (LDH) is a marker of intravascular hemolysis 1

Classification

• Classical PNH: Predominantly hemolytic form with significant intravascular hemolysis 4
• PNH with another bone marrow disorder (often aplastic anemia or myelodysplastic syndrome) 4
• Subclinical PNH: Small PNH clone without clinical manifestations 4

Treatment Options

Complement Inhibitors

• Eculizumab (Soliris) is FDA-approved for PNH treatment to reduce hemolysis by blocking complement activation at C5 6

  • Dosing: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter 6
  • Significantly improves hemoglobin levels, reduces transfusion requirements, and decreases thrombotic risk 5

• Ravulizumab (Ultomiris) is a longer-acting anti-C5 antibody also approved for PNH 7

  • Advantage of less frequent dosing (every 8 weeks) compared to eculizumab 5

• Proximal complement inhibitors (targeting C3, factor B, or factor D):

  • Pegcetacoplan (anti-C3) is approved for patients who remain anemic despite C5 inhibition 1
  • Particularly useful for patients who develop extravascular hemolysis on C5 inhibitors 1

Important Safety Considerations

• Meningococcal vaccination is mandatory before starting complement inhibitor therapy 6

  • Vaccinate against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to starting therapy 6
  • If urgent therapy is needed, provide antibacterial prophylaxis until vaccination 6

• Risk of serious meningococcal infections necessitates enrollment in a Risk Evaluation and Mitigation Strategy (REMS) program 6

Supportive Care

• Red blood cell transfusions for symptomatic anemia 3
• Anticoagulation for thrombotic events 4
• Folic acid supplementation to support erythropoiesis 3

Definitive Treatment

• Allogeneic hematopoietic stem cell transplantation may be curative but carries significant risks 5
  • Generally reserved for patients with severe aplastic anemia component or those who fail complement inhibitor therapy 5

Monitoring and Follow-up

• Regular monitoring of hemoglobin, LDH, and reticulocyte count to assess disease activity and treatment response 1
• Vigilance for signs of thrombosis, which can occur despite treatment 5
• Assessment for breakthrough hemolysis, which may require dose adjustment or change in therapy 5

Complications and Prognosis

• Without treatment, mortality rate is approximately 35% 5
• Complement inhibitor therapy has dramatically improved survival 1
• Major causes of morbidity and mortality include thrombotic events and end-organ damage 5
• Quality of life can be significantly improved with appropriate therapy 1