Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acquired clonal stem cell disorder with complement-mediated intravascular hemolysis, thrombosis, and cytopenias.
Also known as: PNH, paroxysmal nocturnal hemoglobinuria, Marchiafava-Micheli
Overview
Acquired clonal hematopoietic stem cell disorder caused by somatic mutation in the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins (CD55, CD59) on blood cells. Loss of complement regulators triggers intravascular hemolysis, hypercoagulability, and bone marrow dysfunction.
Epidemiology
Rare — incidence ~1-2 per million per year. Median age at diagnosis 30s-40s. No sex predominance. Strongly associated with aplastic anemia and other bone marrow failure syndromes.
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Risk factors
- Pre-existing aplastic anemia or MDS
- No known inherited predisposition (mutation is acquired/somatic)
Pathophysiology
Somatic mutation in PIGA (X-linked) within a hematopoietic stem cell impairs synthesis of the GPI anchor. Progeny cells lack GPI-anchored complement regulators CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis). Unregulated activation of the alternative complement pathway lyses red cells (intravascular hemolysis). Free hemoglobin scavenges nitric oxide → smooth muscle dystonia (esophageal spasm, abdominal pain, erectile dysfunction) and platelet activation contributing to thrombosis.
Clinical presentation
Symptoms
- Fatigue and dyspnea from chronic anemia
- Episodic dark/cola-colored urine — classically first morning void (overnight acidosis enhances complement activity)
- Abdominal, back, or chest pain from smooth muscle dystonia
- Dysphagia, erectile dysfunction
- Unexplained thrombosis — particularly hepatic veins (Budd-Chiari), portal/mesenteric, cerebral venous sinuses, dermal venules
Signs / physical exam
- Pallor, jaundice
- Hepatomegaly with ascites (Budd-Chiari)
- Cytopenias (anemia ± leukopenia, thrombocytopenia)
Classic findings
Coombs-negative intravascular hemolytic anemia with hemoglobinuria, iron deficiency from urinary loss, and atypical-site venous thrombosis.
Differential diagnosis
- Autoimmune hemolytic anemia — Positive direct Coombs; PNH is Coombs-negative
- Aplastic anemia — Pancytopenia with hypocellular marrow; PNH and AA frequently coexist — screen all AA patients
- Myelodysplastic syndrome — Dysplastic morphology, cytogenetic abnormalities; flow cytometry can distinguish
- Hereditary or acquired TTP/HUS — Schistocytes, thrombocytopenia, renal failure; ADAMTS13 activity
- March hemoglobinuria / mechanical hemolysis — Hemoglobinuria after vigorous exercise or mechanical valve; no clonal flow defect
Diagnostic workup
Diagnostic criteria
Flow cytometric demonstration of a GPI-deficient clone (≥1% of granulocytes by FLAER) in a patient with hemolysis, cytopenias, or thrombosis. Clinical category assigned: classic PNH (florid hemolysis, large clone), PNH in setting of marrow failure, or subclinical PNH (clone <1% without symptoms).
Labs
- CBC — anemia ± pancytopenia, often with elevated reticulocytes
- Markers of intravascular hemolysis: LDH markedly elevated, haptoglobin undetectable, indirect bilirubin elevated, free plasma hemoglobin
- Urinalysis — hemoglobinuria and hemosiderinuria (urinary iron loss → iron deficiency)
- Direct antiglobulin test — NEGATIVE
- Flow cytometry on peripheral blood — DIAGNOSTIC: deficiency of CD55 and CD59 on RBCs; FLAER (fluorescein-labeled aerolysin) binding test on granulocytes/monocytes is most sensitive
- Bone marrow biopsy if cytopenias or suspected aplastic anemia
Imaging
- Doppler ultrasound or MR venography of abdomen if Budd-Chiari or portal vein thrombosis suspected
- MR/MRV brain for cerebral venous sinus thrombosis
Diagnostic algorithm
flowchart TD
A[Coombs-negative<br/>hemolytic anemia<br/>± thrombosis<br/>± cytopenias] --> B[Flow cytometry<br/>peripheral blood]
B --> C[FLAER on granulocytes<br/>CD55/CD59 on RBCs]
C -->|GPI-deficient<br/>clone present| D[PNH diagnosis]
D --> E[Meningococcal vax<br/>+ prophylaxis]
E --> F[Eculizumab or<br/>ravulizumab]
F --> G{Breakthrough<br/>hemolysis?}
G -->|Yes| H[Pegcetacoplan<br/>or iptacopan]
G -->|No| I[Continue + monitor]
D --> J{Marrow failure?}
J -->|Yes| K[Allo-HSCT<br/>only cure]Treatment
First-line
- Terminal complement inhibition — eculizumab (anti-C5 monoclonal antibody) or ravulizumab (long-acting anti-C5)
- Meningococcal vaccination (MenACWY + MenB) at least 2 weeks before C5 inhibitor initiation; antibiotic prophylaxis (penicillin or ciprofloxacin) for vaccine lag period
- Folic acid supplementation; iron repletion as needed
- Therapeutic anticoagulation for documented thrombosis
Classic hemolytic PNH
- Eculizumab or ravulizumab
- Add proximal complement inhibitor (pegcetacoplan — C3 inhibitor) for breakthrough hemolysis on anti-C5 therapy
- Newer agents: iptacopan (oral factor B inhibitor), danicopan (factor D inhibitor) for residual hemolysis
PNH with bone marrow failure
- Immunosuppression (ATG + cyclosporine) for associated aplastic anemia
- Allogeneic hematopoietic stem cell transplant — only curative option
Thrombosis
- Long-term anticoagulation (warfarin or DOAC — apixaban, rivaroxaban) PLUS complement inhibition
- Consider catheter-directed thrombolysis or TIPS for acute Budd-Chiari
Second-line / adjunct
- Allogeneic stem cell transplantation — only curative therapy; reserved for transplant-eligible patients with marrow failure or refractory disease
- Primary thromboprophylaxis with anticoagulation may be considered for large clones (>50%) without complement inhibition
Complications
- Thrombosis (leading cause of mortality) — Budd-Chiari, portal, cerebral, mesenteric, dermal
- Chronic kidney disease from recurrent hemoglobinuria and microvascular thrombosis
- Pulmonary hypertension from chronic intravascular hemolysis
- Progression to aplastic anemia, MDS, or AML
- Meningococcal sepsis (Neisseria meningitidis) in patients on terminal complement inhibitors
PANCE pearls
- Despite the name, hemolysis is continuous — nocturnal hemoglobinuria reflects concentration of overnight breakdown products.
- Unexplained thrombosis at unusual sites (especially hepatic veins) in a young adult should prompt PNH screening.
- Screen all aplastic anemia and unexplained Coombs-negative hemolysis patients with flow cytometry.
- Anti-C5 therapy controls intravascular hemolysis but extravascular (C3-mediated) hemolysis can persist — pegcetacoplan or oral factor B/D inhibitors address this.
- Meningococcal vaccination is mandatory before starting eculizumab/ravulizumab; document and provide patient wallet card.
References
- International PNH Interest Group — Parker C et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106:3699-3709 (with subsequent updates).
- FDA approvals — Eculizumab (Soliris) approved 2007; ravulizumab (Ultomiris) 2018; pegcetacoplan (Empaveli) 2021; iptacopan (Fabhalta) 2023.
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