How should paroxysmal nocturnal hemoglobinuria (PNH) be diagnosed and managed in a symptomatic adult, including the use of complement inhibitors (eculizumab or ravulizumab), meningococcal vaccination, anticoagulation, supportive care, and consideration of hematopoietic stem‑cell transplantation?

Paroxysmal Nocturnal Hemoglobinuria: Diagnosis and Management

Diagnostic Approach

Flow cytometry to detect GPI-anchored protein deficiency (CD55 and CD59) on peripheral blood cells is the definitive diagnostic test for PNH and should be performed in all suspected cases. 1, 2

Clinical Presentations Requiring PNH Testing

• Unexplained intravascular hemolysis with negative direct antiglobulin test (Coombs negative), elevated LDH, reduced haptoglobin, and hemoglobinuria 2, 3
• Venous thrombosis in unusual sites, particularly splanchnic vessels (hepatic, portal, mesenteric veins) or Budd-Chiari syndrome—9-19% of Budd-Chiari patients have underlying PNH 1, 2
• Cytopenias with bone marrow failure syndromes, including aplastic anemia or hypoplastic myelodysplastic syndrome with normal cytogenetics 1, 2
• Schistocytes on peripheral smear with non-immune hemolytic anemia, indicating active intravascular hemolysis 3

Initial Laboratory Evaluation

• Complete blood count with differential, reticulocyte count, and peripheral blood smear examination 1, 2
• Hemolysis markers: LDH (typically markedly elevated), haptoglobin (reduced/absent), indirect bilirubin (elevated), free hemoglobin 2, 3
• Direct antiglobulin test (negative in PNH) 2, 3
• Renal function tests and coagulation profile 2
• Flow cytometry for GPI-anchored proteins (CD55, CD59) on granulocytes, monocytes, and red blood cells—this is the gold standard diagnostic test 1, 2, 4

Additional Testing for Specific Scenarios

• For patients with thrombosis: JAK2V617F mutation testing to exclude myeloproliferative neoplasms, and thrombophilia screening 1, 2
• For patients with cytopenias: Bone marrow aspiration and biopsy with cytogenetic analysis to evaluate for aplastic anemia or myelodysplastic syndrome 1, 2
• For splanchnic vein thrombosis: Routine PNH testing is mandatory, especially in Budd-Chiari syndrome 1, 2

Interpretation of Clone Size

• PNH clone >60% of granulocytes indicates significantly higher risk of thrombosis and hemolysis, requiring more aggressive management 2, 3
• PNH can coexist with aplastic anemia or myelodysplastic syndrome 2, 4

Management Strategy

Meningococcal Vaccination (Critical First Step)

All patients must receive meningococcal vaccination at least 2 weeks before initiating complement inhibitor therapy, or receive prophylactic antibiotics until 2 weeks post-vaccination. 5 This is non-negotiable due to the life-threatening risk of meningococcal sepsis with complement inhibition.

• Administer vaccines against serogroups A, C, W, Y, and B 5
• Prophylactic antibiotics (typically penicillin or macrolide) are required if vaccination cannot be completed 2 weeks prior to treatment initiation 5

Complement Inhibitor Therapy

Ravulizumab or eculizumab should be initiated in symptomatic PNH patients with hemolytic anemia, history of thrombosis, or significant symptoms affecting quality of life. 5, 6, 7

C5 Inhibitor Selection and Dosing

Ravulizumab is preferred over eculizumab due to less frequent dosing (every 8 weeks vs. every 2 weeks), reducing treatment burden and risk of breakthrough hemolysis from missed doses 5, 6, 7

• Ravulizumab dosing (weight-based): Loading dose followed by maintenance every 8 weeks intravenously 5
• Eculizumab dosing: 600 mg weekly × 4 weeks, then 900 mg every 2 weeks 8, 6
• Both agents effectively reduce thrombosis risk, improve survival to match healthy controls, and enhance quality of life 6, 7

Monitoring on C5 Inhibitor Therapy

• LDH levels to assess intravascular hemolysis control 5, 6
• Hemoglobin and transfusion requirements 5, 6, 9
• Approximately 30% of patients develop clinically significant extravascular hemolysis on C5 inhibitors, manifesting as persistent anemia and transfusion dependence despite controlled intravascular hemolysis 6

Management of Extravascular Hemolysis on C5 Inhibitors

For patients with ongoing transfusion requirements or symptomatic anemia despite C5 inhibitor therapy, switch to alternative pathway complement inhibitors (pegcetacoplan, iptacopan) or add danicopan to existing C5 inhibitor 6

• Pegcetacoplan (C3 inhibitor): subcutaneous twice weekly 6
• Iptacopan (factor B inhibitor): oral twice daily 6
• Danicopan (factor D inhibitor): oral three times daily as add-on to C5 inhibitor 6

Anticoagulation Management

Continue existing anticoagulation therapy in patients with history of thrombosis; complement inhibitor therapy does not replace anticoagulation. 5 The effect of withdrawing anticoagulation during complement inhibitor treatment is unknown and potentially dangerous 5.

• Patients with prior thrombosis should remain on indefinite anticoagulation 5
• Complement inhibitors reduce but do not eliminate thrombosis risk—breakthrough events still occur in 10-23.5% of patients on long-term C5 inhibitor therapy 9

Supportive Care

• Transfusion support: Administer packed red blood cells for symptomatic anemia; all blood products should be irradiated and filtered in patients with concurrent bone marrow failure 1
• Folic acid supplementation for chronic hemolysis 4
• Iron supplementation cautiously, as it may exacerbate hemolysis in some patients 4

Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation is the only curative therapy and should be considered for:

• Patients with severe bone marrow failure (severe aplastic anemia with PNH clone) 1
• Young patients with suitable donors who have life-threatening disease despite complement inhibitor therapy 4
• Patients with refractory disease or intolerance to complement inhibitors 4

HSCT is NOT first-line therapy due to transplant-related morbidity and mortality; complement inhibitors are preferred initial management 4, 6

Treatment Discontinuation Monitoring

If complement inhibitor therapy is discontinued, monitor closely for at least 16 weeks (PNH) or 12 months (if bone marrow failure component) for hemolysis recurrence. 5

• Monitor LDH, hemoglobin, PNH clone size, and symptoms (fatigue, hemoglobinuria, abdominal pain, dyspnea, thrombosis) 5
• Consider restarting therapy if hemolysis recurs 5

Management of Infusion Reactions

If infusion-related reactions occur (lower back pain, abdominal pain, hypotension, rigors), interrupt infusion and provide supportive measures; reactions do not typically require permanent discontinuation. 5 These occur in 1-7% of patients receiving ravulizumab or eculizumab 5.

Common Pitfalls to Avoid

• Never delay meningococcal vaccination—meningococcal sepsis is rapidly fatal and the most serious complication of complement inhibitor therapy 5
• Do not discontinue anticoagulation when starting complement inhibitors in patients with prior thrombosis 5
• Do not assume C5 inhibitors eliminate all hemolysis—monitor for extravascular hemolysis with persistent anemia and transfusion needs 6, 9
• Do not miss PNH diagnosis in Budd-Chiari syndrome—routine flow cytometry testing is mandatory 1, 2