Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal hematopoietic stem cell disorder caused by somatic mutations in the X-linked PIGA gene, resulting in deficiency of GPI-anchored complement regulatory proteins (CD55 and CD59) on blood cell surfaces. This renders red blood cells exquisitely susceptible to complement-mediated intravascular hemolysis, with a clinical triad of hemolytic anemia, thrombophilia, and bone marrow failure. [1-2] Estimated prevalence is <10 cases per million population. [2]
The following figure illustrates the complement cascade and the loss of CD55/CD59 in PNH, as well as the therapeutic targets of current complement inhibitors:
1. History
- Dark/cola-colored urine, classically most prominent in the morning upon waking (nocturnal hemoglobinuria) — present at some point in >90% of patients, ~50% present with this sign [4]
- Fatigue, weakness, exercise intolerance (often the most debilitating symptom)
- Abdominal pain (~35% during paroxysms) — due to smooth muscle dystonia from nitric oxide scavenging by free hemoglobin, not always thrombotic [4]
- Dysphagia/esophageal spasm (~23% incidence) [4]
- Erectile dysfunction in males [2]
- Shortness of breath
- Triggers for paroxysms: infections, surgery, trauma, drugs, physical exertion, stress, pregnancy [4-5]
- Duration of hemoglobinuria episodes: typically 3–7 days, but can be prolonged [4]
- History of aplastic anemia or MDS (close association) [6]
- Timing: typically diagnosed in young adulthood (median age 24–41 years) [7]
2. Alarm Features
- Budd-Chiari syndrome (hepatic vein thrombosis) — the most frequent thrombotic manifestation [8-9]
- Thrombosis at unusual sites: mesenteric, cerebral, dermal veins [10-11]
- Pulmonary embolism
- Acute kidney injury from hemoglobinuria or renal hemosiderosis [12-13]
- Severe hemolytic crisis with hemoglobin dropping precipitously
- Signs of pulmonary hypertension (dyspnea, right heart failure) [11]
- Pancytopenia suggesting bone marrow failure
- Progression to AML (~5% of patients) [6]
- Breakthrough hemolysis on complement inhibitor therapy (sudden hemoglobinuria, LDH spike, hemoglobin drop) [2]
3. Medications
FDA-Approved Complement Inhibitors
- Terminal (C5) inhibitors:
- Eculizumab (Soliris) — IV every 2 weeks; PNH dosing: 600 mg weekly × 4 weeks, then 900 mg every 2 weeks [14-15]
- Ravulizumab (Ultomiris) — IV every 8 weeks (long-acting C5 inhibitor) [14]
- Crovalimab (Piasky) — subcutaneous anti-C5 antibody for patients ≥13 years/≥40 kg [14]
- Eculizumab biosimilars (Epysqli, Bkemv) [14]
- Proximal complement inhibitors (address extravascular hemolysis):
- Pegcetacoplan (Empaveli) — C3 inhibitor, subcutaneous [14][16]
- Iptacopan (Fabhalta) — oral factor B inhibitor, the only oral monotherapy approved for PNH [14][17]
- Danicopan (Voydeya) — oral factor D inhibitor, approved as add-on to eculizumab/ravulizumab for extravascular hemolysis [14][18]
Critical medication safety
- ⚠️ Meningococcal vaccination (MenACWY + MenB) is mandatory at least 2 weeks before starting any complement inhibitor [15][19-20]
- Consider antibiotic prophylaxis (penicillin; ciprofloxacin or azithromycin if allergic) in addition to vaccination, especially if urgent initiation is needed [19][21]
- Meningococcal infection risk remains elevated even in vaccinated patients (~1,000–2,000-fold increased risk) [22-23]
- Folic acid supplementation for chronic hemolysis
- Iron supplementation may be needed (chronic urinary iron loss from hemosiderinuria) but monitor carefully — iron repletion can trigger hemolytic paroxysms by releasing reticulocytes
- Anticoagulation: warfarin, DOACs, or LMWH for thrombotic events; DOACs appear safe and effective in PNH [8]
Contraindicated/Caution
- Complement inhibitors are contraindicated in patients with unresolved serious Neisseria meningitidis infection [15]
- Abrupt discontinuation of complement inhibitors can trigger severe rebound hemolysis
4. Diet
- Iron-rich foods may be beneficial given chronic urinary iron losses, but iron supplementation should be physician-guided
- Folic acid–rich foods (leafy greens) to support erythropoiesis
- Adequate hydration, especially during hemolytic paroxysms, to protect renal function and reduce hemoglobin precipitation in tubules [12]
- No specific dietary triggers are established, but infections (including foodborne) can precipitate paroxysms
5. Review of Systems
- Hematologic: fatigue, pallor, jaundice, dark urine, bleeding, bruising
- GI: abdominal pain, dysphagia, nausea (smooth muscle dystonia) [4]
- Genitourinary: erectile dysfunction, dark urine, decreased urine output [4]
- Neurologic: headache (cerebral vein thrombosis), cognitive impairment from chronic anemia
- Pulmonary: dyspnea (anemia, pulmonary hypertension, PE) [11]
- Cardiovascular: chest pain, tachycardia
- Constitutional: recurrent infections (leukopenia)
6. Collateral History and Family History
- PNH is an acquired (not inherited) disorder — no familial pattern [5]
- Prior history of aplastic anemia or MDS is critical — PNH clones are found in 12–18% of aplastic anemia patients [24]
- Transfusion history
- History of unexplained cytopenias or Coombs-negative hemolytic anemia
- Social context: impact on quality of life, work capacity, and mental health due to chronic disease burden
7. Risk Factors
- Aplastic anemia — strongest association; PNH clones detected in up to 50% of AA patients on follow-up [6][24]
- Myelodysplastic syndromes [25]
- Prior immunosuppressive therapy for bone marrow failure
- Large PNH clone size (≥50% GPI-deficient granulocytes) correlates with higher thrombotic risk [26-27]
- LDH ≥1.5× ULN with ≥2 high disease activity criteria increases thrombotic risk [26]
- Pregnancy and postpartum period
- Infections, surgery, and other complement-activating stressors precipitate paroxysms [4]
8. Differential Diagnosis
- Autoimmune hemolytic anemia (AIHA) — Coombs-positive (PNH is Coombs-negative); distinguish by DAT and flow cytometry
- Thrombotic thrombocytopenic purpura (TTP)/Hemolytic uremic syndrome (HUS) — schistocytes on smear, ADAMTS13 activity, renal failure pattern [28]
- Aplastic anemia — may coexist; pancytopenia without hemolysis predominance
- Myelodysplastic syndromes — dysplastic morphology, cytogenetic abnormalities
- March hemoglobinuria — exercise-related, transient
- Cold agglutinin disease — Coombs-positive for C3d
- G6PD deficiency — episodic hemolysis, enzyme assay diagnostic
- Budd-Chiari syndrome from other causes — myeloproliferative neoplasms, hypercoagulable states
- Sickle cell disease — hemoglobin electrophoresis
9. Past Medical History
- Prior aplastic anemia or MDS (most important)
- Previous thrombotic events, especially at unusual sites
- History of iron deficiency anemia (may be the initial presentation due to chronic urinary iron loss) [13]
- Transfusion dependence
- Prior bone marrow biopsy results
- Vaccination history (meningococcal vaccines critical before complement inhibitor therapy)
- Pregnancy history (PNH increases maternal/fetal risk)
10. Physical Exam
- Vital signs: tachycardia, hypotension (if acute hemolytic crisis)
- General: pallor, jaundice, scleral icterus
- Abdomen: hepatosplenomegaly (extravascular hemolysis, Budd-Chiari), tenderness (smooth muscle dystonia or thrombosis)
- Skin: petechiae, purpura (thrombocytopenia), pallor
- Cardiovascular: flow murmur (anemia), signs of right heart failure (pulmonary hypertension)
- Extremities: edema (DVT, hepatic vein thrombosis)
- Neurologic: focal deficits if cerebral venous thrombosis
11. Lab Studies
Diagnostic
- Flow cytometry (gold standard): FLAER + GPI-anchored protein markers (CD55, CD59, CD24, CD14) on granulocytes, monocytes, and RBCs — detects GPI-deficient clones [24][29-30]
- Granulocyte/monocyte analysis with FLAER is more sensitive than RBC analysis (RBC clone size underestimates due to hemolysis and transfusions) [31]
- Type III cells = complete GPI deficiency; Type II = partial deficiency [32]
Hemolysis markers
- LDH — markedly elevated (often >2–3× ULN; can reach 25× during paroxysms); most reliable marker of intravascular hemolysis [4]
- Haptoglobin — undetectable
- Indirect bilirubin — elevated
- Reticulocyte count — elevated (unless bone marrow failure)
- Direct antiglobulin test (DAT/Coombs) — negative (distinguishes from AIHA)
- Plasma free hemoglobin — elevated
Additional
- CBC with differential: anemia (may be macrocytic from reticulocytosis), leukopenia, thrombocytopenia [6]
- Iron studies: often iron deficient from chronic urinary losses (ferritin low, TIBC high)
- Urine hemosiderin — positive (chronic marker)
- Renal function (BUN/Cr) — may show AKI or CKD from hemosiderin deposition [12-13]
- Coagulation studies, D-dimer if thrombosis suspected
- Bone marrow biopsy if bone marrow failure suspected [11]
12. Imaging
- Doppler ultrasound of abdomen — first-line if Budd-Chiari or mesenteric/portal vein thrombosis suspected
- CT angiography — for pulmonary embolism, cerebral venous sinus thrombosis, or abdominal vein thrombosis
- MRI abdomen — can detect hepatic vein thrombosis and renal cortical hemosiderin deposition (low T2 signal in kidneys) [12]
- Echocardiography — assess for pulmonary hypertension (elevated RVSP)
- MRI brain with venography — if cerebral venous thrombosis suspected
- Imaging is unnecessary for diagnosis of PNH itself (flow cytometry is diagnostic)
13. Special Tests
- Flow cytometry with FLAER — the definitive diagnostic test; has replaced the Ham test (acidified serum lysis test) and sucrose lysis test [6][29]
- PNH clone size quantification — granulocyte clone size is most clinically relevant for risk stratification and treatment decisions [26-27]
- Bone marrow aspirate and biopsy with cytogenetics — indicated when bone marrow failure is suspected or to exclude MDS/AML [11]
- PIGA gene mutation analysis — confirmatory but not routinely required for clinical diagnosis
Screening indications for PNH by flow cytometry: [11][25][27]
- Coombs-negative hemolytic anemia
- Aplastic anemia or hypoplastic MDS
- Unexplained thrombosis at unusual sites (especially Budd-Chiari)
- Unexplained cytopenias
- Hemoglobinuria
14. ECG
- ECG is not a primary diagnostic tool for PNH
- Indicated if chest pain, dyspnea, or tachycardia to rule out PE-related right heart strain (S1Q3T3, right axis deviation, T-wave inversions in right precordial leads)
- Sinus tachycardia from severe anemia
- Arrhythmias from electrolyte disturbances in acute hemolytic crisis
15. Assessment
PNH is classified into three categories per the International PNH Interest Group: [11]
- Classic PNH — large clone, predominant hemolysis, minimal or no bone marrow failure
- PNH in the setting of another bone marrow disorder (e.g., PNH/aplastic anemia, PNH/MDS)
- Subclinical PNH — small clone detected on screening, no clinical or laboratory evidence of hemolysis
Severity stratification depends on
- Clone size (granulocyte clone ≥50% = high risk for thrombosis) [26-27]
- LDH level and degree of hemolysis
- Transfusion dependence
- Thrombotic history
- Degree of bone marrow failure
Complications to consider: thrombosis (leading cause of death historically), renal failure, pulmonary hypertension, progression to MDS/AML, iron deficiency, and quality-of-life impairment. [1][6][11]
16. Treatment Plan
Initial stabilization (acute hemolytic crisis)
- Aggressive IV hydration to protect renal function
- Transfusion of packed RBCs as needed (use leukoreduced, irradiated products)
- Treat precipitating cause (infection, etc.)
- Anticoagulation if acute thrombosis
Complement inhibitor therapy (mainstay for hemolytic PNH): [33-35]
- First-line: Terminal C5 inhibitors — ravulizumab (preferred for convenience, q8 weeks IV) or eculizumab (q2 weeks IV) or crovalimab (subcutaneous)
- Controls intravascular hemolysis and virtually eliminates thrombotic risk [16][33]
- Does NOT treat bone marrow failure component
- For persistent anemia/extravascular hemolysis on C5 inhibitors:
- Switch to pegcetacoplan (C3 inhibitor) or iptacopan (oral factor B inhibitor) as monotherapy [16-17]
- Add danicopan (factor D inhibitor) to existing C5 inhibitor [14][18]
- Pre-treatment requirements: Meningococcal vaccination (MenACWY + MenB) ≥2 weeks before first dose; consider antibiotic prophylaxis [15][19]
Supportive care
- Folic acid supplementation
- Iron supplementation (with caution — can trigger hemolysis)
- Erythropoiesis-stimulating agents if concurrent bone marrow failure
- Anticoagulation for thrombotic events (DOACs appear safe) [8]
Curative therapy
- Allogeneic hematopoietic stem cell transplant[1][33][36]
The following figure illustrates the complement cascade therapeutic targets for PNH:
17. Disposition
Admission criteria
- Acute hemolytic crisis with hemodynamic instability or severe anemia
- Acute thrombosis (Budd-Chiari, PE, cerebral venous thrombosis, mesenteric thrombosis)
- Acute kidney injury
- Severe breakthrough hemolysis on complement inhibitor therapy
- Sepsis or meningococcal infection
Observation indications
- Moderate hemolytic exacerbation with stable vitals
- New diagnosis requiring urgent workup and initiation of complement inhibitor
Discharge criteria
- Hemodynamically stable, hemoglobin stable or improving
- Hemolysis controlled (LDH trending down)
- Adequate renal function
- Complement inhibitor therapy initiated or arranged
- Meningococcal vaccination administered or scheduled
Specialist consultation triggers
- Hematology — all patients with confirmed or suspected PNH
- Nephrology — AKI, CKD, or renal hemosiderosis
- Hepatology/IR — Budd-Chiari syndrome
- Neurology — cerebral venous thrombosis
- Transplant hematology — candidates for allogeneic HSCT
18. Follow Up / Return Precautions
Follow-up timing
- Newly diagnosed: hematology follow-up within 1–2 weeks
- On complement inhibitors: regular monitoring per infusion schedule (q2 weeks for eculizumab, q8 weeks for ravulizumab); LDH, CBC, reticulocyte count at each visit
- Clone size monitoring by flow cytometry every 6–12 months [30]
Symptoms requiring immediate reassessment
- Return of dark urine or worsening hemoglobinuria (breakthrough hemolysis)
- Severe abdominal pain (thrombosis vs. smooth muscle dystonia)
- Sudden headache, vision changes, or focal neurologic deficits (cerebral venous thrombosis)
- Fever, neck stiffness, rash (meningococcal infection — medical emergency)
- Chest pain or acute dyspnea (PE)
- Decreased urine output (AKI)
Patient counseling points
- Carry a patient safety card indicating complement inhibitor use and meningococcal infection risk [20]
- Seek emergency care immediately for fever, especially with rash or neck stiffness
- Do not miss scheduled complement inhibitor infusions — missed doses can trigger rebound hemolysis
- Inform all healthcare providers about PNH diagnosis and complement inhibitor therapy before any procedures or vaccinations
Expected recovery course
- Complement inhibitors dramatically improve quality of life, reduce transfusion needs, and normalize LDH in most patients [16][33]
- Median survival has improved significantly in the complement inhibitor era, approaching that of the general population with appropriate treatment [1]
- Some patients achieve spontaneous remission (rare) [5]
- Lifelong monitoring is required given the chronic nature of the disease
References
1. Paroxysmal Nocturnal Hemoglobinuria. — Godby RC, Shah S. Mayo Clinic Proceedings. 2025.
2. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. — Notaro R, Luzzatto L. The New England Journal of Medicine. 2022.
3. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. — Devalet B, Mullier F, Chatelain B, Dogné JM, Chatelain C. European Journal of Haematology. 2015.
4. The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin: A Novel Mechanism of Human Disease. — Rother RP, Bell L, Hillmen P, Gladwin MT. The Journal of the American Medical Association. 2005.
5. Paroxysmal nocturnal hemoglobinuria. — National Library of Medicine (MedlinePlus) 2022.
6. Red Cells II: Acquired Anaemias and Polycythaemia. — Provan D, Weatherall D. Lancet. 2000.
7. Clinical Characteristics and Management of Paroxysmal Nocturnal Haemoglobinuria in Latin America: A Narrative Review. — Goldschmidt V, Apodaca EI, Gálvez KM, Wannesson B, Scheinberg P. Annals of Hematology. 2025.
8. Paroxysmal Nocturnal Hemoglobinuria-Related Thrombosis in the Era of Novel Therapies: A 2043-Patient-Year Analysis. — Gurnari C, Awada H, Pagliuca S, et al. Blood. 2024.
9. Mechanisms and Clinical Implications of Thrombosis in Paroxysmal Nocturnal Hemoglobinuria. — Van Bijnen ST, Van Heerde WL, Muus P. Journal of Thrombosis and Haemostasis : JTH. 2012.
10. Thromboembolic Events in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH): Real World Data of a Greek Nationwide Multicenter Retrospective Study. — Chatzileontiadou S, Hatjiharissi E, Angelopoulou M, et al. Frontiers in Oncology. 2023.
11. Eculizumab for Treating Patients With Paroxysmal Nocturnal Hemoglobinuria. — Martí-Carvajal AJ, Anand V, Cardona AF, Solà I. The Cochrane Database of Systematic Reviews. 2014.
12. Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist's Opinion. — Gembillo G, Siligato R, Cernaro V, Santoro D. Journal of Clinical Medicine. 2020.
13. Hemosiderin Induced Acute Kidney Injury Requiring Hemodialysis in Patients With Paroxysmal Nocturnal Hemoglobinuria: A Case Report. — Choi H, Yim H, Lee MJ. Medicine. 2023.
14. FDA Orange Book. — FDA Orange Book. 2026.
15. FDA Drug Label. — Updated date: 2026-04-15. Food and Drug Administration.
16. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. — Hillmen P, Szer J, Weitz I, et al. The New England Journal of Medicine. 2021.
17. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. — Peffault de Latour R, Röth A, Kulasekararaj AG, et al. The New England Journal of Medicine. 2024.
18. Addition of Danicopan to Ravulizumab or Eculizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria and Clinically Significant Extravascular Haemolysis (ALPHA): A Double-Blind, Randomised, Phase 3 Trial. — Lee JW, Griffin M, Kim JS, et al. The Lancet. Haematology. 2023.
19. Prevention and Treatment of Cancer-Related Infections. — Updated 2026-03-11. National Comprehensive Cancer Network.
20. FDA Drug Label. — Updated date: 2025-12-01. Food and Drug Administration.
21. New Dosing Interval and Schedule for the Bexsero MenB-4C Vaccine: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, October 2024. — Schillie S, Loehr J, Chen WH, et al. MMWR. Morbidity and Mortality Weekly Report. 2024.
22. Characteristics of and Meningococcal Disease Prevention Strategies for Commercially Insured Persons Receiving Eculizumab in the United States. — Bozio CH, Isenhour C, McNamara LA. PloS One. 2020.
23. High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine. — McNamara LA, Topaz N, Wang X, et al. MMWR. Morbidity and Mortality Weekly Report. 2017.
24. Multiparameter FLAER-based Flow Cytometry for Screening of Paroxysmal Nocturnal Hemoglobinuria Enhances Detection Rates in Patients With Aplastic Anemia. — Sachdeva MU, Varma N, Chandra D, et al. Annals of Hematology. 2015.
25. Myelodysplastic Syndromes. — Updated 2026-01-12. National Comprehensive Cancer Network.
26. Risk Factors for Thromboembolic Events in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH): A Nested Case-Control Study in the International PNH Registry. — Höchsmann B, Peffault de Latour R, Hill A, et al. Annals of Hematology. 2023.
27. Aplastic Anemia. — Young NS. The New England Journal of Medicine. 2018.
28. Paroxysmal Nocturnal Hemoglobinuria Masquerading as Hemolytic Uremic Syndrome: A Case Report. — Gao M, Liu B, Yao J, Huang F. Frontiers in Medicine. 2025.
29. The Use of Monoclonal Antibodies and Flow Cytometry in the Diagnosis of Paroxysmal Nocturnal Hemoglobinuria. — Hall SE, Rosse WF. Blood. 1996.
30. Paroxysmal Nocturnal Hemoglobinuria (PNH): Higher Sensitivity and Validity in Diagnosis and Serial Monitoring by Flow Cytometric Analysis of Reticulocytes. — Höchsmann B, Rojewski M, Schrezenmeier H. Annals of Hematology. 2011.
31. Use of a FLAER-based WBC Assay in the Primary Screening of PNH Clones. — Sutherland DR, Kuek N, Azcona-Olivera J, et al. American Journal of Clinical Pathology. 2009.
32. How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. — Patriquin CJ, Kiss T, Caplan S, et al. European Journal of Haematology. 2019.
33. How I Treat Paroxysmal Nocturnal Hemoglobinuria. — Brodsky RA. Blood. 2021.
34. Pharmacological Therapies in Paroxysmal Nocturnal Haemoglobinuria: Focus on Complement Inhibition. — Kelly RJ, Holt M, Szer J. Drugs. 2025.
35. The Varieties of Therapeutic Experience: Navigating Treatment Options for Patients With PNH. — Bienz M, Patriquin CJ. Hematology. American Society of Hematology. Education Program. 2025.
36. Paroxysmal Nocturnal Hemoglobinuria. — Brodsky RA. Blood. 2014.
37. A growing panoply of options for patients with paroxysmal nocturnal hemoglobinuria. — Young DJ. American Journal of Hematology. 2024.