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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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.
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
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]
PNH diagnostic flow and treatment ladder anchored on terminal complement inhibition.
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).
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