Paroxysmal Nocturnal Hemoglobinuria (PNH): Overview and Treatment
For patients with PNH, complement inhibitor therapy with eculizumab or ravulizumab is the primary treatment to reduce hemolysis and prevent life-threatening thrombotic complications, with newer proximal complement inhibitors offering superior hemoglobin improvement for patients with residual anemia. 1, 2, 3
Disease Overview
PNH is an acquired clonal hematopoietic stem cell disorder caused by a somatic mutation in the PIGA gene, resulting in deficiency of GPI-anchored complement regulatory proteins (CD55 and CD59) on blood cell membranes. 4, 3 This renders cells susceptible to complement-mediated destruction, producing the characteristic triad of:
- Intravascular hemolytic anemia with chronic hemolysis and potential for acute exacerbations 4, 5
- Thrombosis (the leading cause of mortality), particularly in unusual sites like splanchnic veins 6, 4
- Bone marrow failure with cytopenias, often associated with aplastic anemia or myelodysplastic syndrome 7, 4
Natural history without treatment shows median survival of 10 years with 28% mortality from thrombosis or hemorrhage. 8
Diagnostic Approach
Clinical Presentations Requiring PNH Testing
- Unexplained intravascular hemolysis with negative direct antiglobulin test 7
- Venous thrombosis in unusual sites, especially splanchnic veins (Budd-Chiari syndrome occurs in 9-19% of PNH patients) 7, 6
- Cytopenias with bone marrow failure syndromes, particularly hypoplastic MDS with normal cytogenetics in young patients 7
Diagnostic Workup
Initial laboratory evaluation: 7
- Complete blood count with differential and reticulocyte count
- Peripheral blood smear for hemolysis evidence
- Hemolysis markers: LDH (elevated), haptoglobin (low), bilirubin, free hemoglobin
- Renal function and coagulation profile
Confirmatory testing: High-sensitivity flow cytometry on peripheral blood to detect GPI-anchored protein deficiency on granulocytes and red blood cells 7
For patients with cytopenias: Bone marrow aspiration, biopsy, and cytogenetic analysis 7
Treatment Strategy
First-Line: Terminal Complement (C5) Inhibitors
FDA-approved C5 inhibitors are the established standard of care: 1, 2, 1
Eculizumab (Soliris) - Intravenous administration 1
- Loading: 600 mg weekly × 4 weeks
- Maintenance: 900 mg at week 5, then 900 mg every 2 weeks
Ravulizumab (Ultomiris) - Intravenous administration with less frequent dosing 2
- Loading: Weight-based dosing
- Maintenance: Every 8 weeks
Crovalimab - Subcutaneous administration every 4 weeks 9
Benefits of C5 inhibitors: 5, 9
- Reduced intravascular hemolysis
- Dramatically reduced thrombosis risk
- Improved survival to near-normal life expectancy
- Improved quality of life
- Reduced transfusion requirements
Critical Safety Requirement: Meningococcal Vaccination
All patients MUST receive meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before starting complement inhibitor therapy. 1 If urgent therapy is needed, provide antibacterial prophylaxis and vaccinate as soon as possible. 1 Life-threatening and fatal meningococcal infections have occurred with complement inhibitors. 1
Second-Line: Proximal Complement Inhibitors
For patients with clinically significant residual anemia or transfusion dependence despite C5 inhibition (approximately 30% of patients), proximal complement inhibitors targeting the alternative pathway offer superior hemoglobin improvement: 3, 5, 9
Pegcetacoplan - C3 inhibitor, subcutaneous twice weekly 9
- Addresses both intravascular and extravascular hemolysis
- Demonstrated superior hemoglobin increases and transfusion avoidance
Iptacopan - Factor B inhibitor, oral twice daily 9
- Controls both intravascular and extravascular hemolysis
- Effective in both C5 inhibitor-naive and C5 inhibitor-experienced patients
Danicopan - Factor D inhibitor, oral three times daily 9
- Used as add-on therapy to eculizumab or ravulizumab
- Combination approach targeting both terminal complement and alternative pathway
Important caveat: Breakthrough hemolysis with strong complement triggers may be more severe with alternative pathway inhibitor monotherapy compared to C5 inhibitors. 9 Real-world data on comparative breakthrough rates are still emerging. 9
Thrombosis Management
Anticoagulation Strategy
Patients with PNH clone size >60% of granulocytes have significantly higher thrombosis risk. 6
For established thrombosis: 6
- Immediate anticoagulation required
- Budd-Chiari syndrome or portal vein thrombosis: Indefinite anticoagulation recommended even with complement inhibitor therapy
- Cerebral venous thrombosis: Immediate anticoagulation plus C5 inhibitor therapy with neurological evaluation
Hepatology consultation for TIPS consideration in selected Budd-Chiari cases 6
Special Populations
Pregnancy: Associated with high maternal mortality; specialized management required if pregnancy occurs 6
Surgery: Requires careful planning with preference for epidural over general anesthesia when possible 6
Monitoring and Breakthrough Hemolysis
Breakthrough hemolysis can occur with any complement inhibitor during strong complement triggers (infections, surgery, pregnancy). 9 Patients require close monitoring for signs of hemolysis recurrence, including:
- Rising LDH
- Falling hemoglobin
- Increasing transfusion requirements
- Dark urine
Management of breakthrough: May require temporary dose intensification or addition of proximal complement inhibitor. 3, 5