Paroxysmal nocturnal haemoglobinuria
Description
- Acquired clonal haematopoietic stem cell disorder: somatic PIGA mutation -> no GPI anchor -> loss of all GPI-anchored surface proteins
- Triad
- Intravascular haemolysis (complement-mediated)
- Thrombosis - at unusual sites
- Marrow failure - overlaps aplastic anaemia
- The name is misleading: haemolysis is continuous, not paroxysmal, and nocturnal haemoglobinuria is seen in a minority
Three clinical categories
| Classical PNH | Florid haemolysis, large clone, cellular marrow |
| PNH in the setting of another marrow failure | Aplastic anaemia or MDS with a PNH clone |
| Subclinical | Small clone, no haemolysis - do not treat |
Epidemiology
- Rare: ~1-1.5 per million/yr; prevalence ~15 per million
- Any age; median diagnosis in the 30s-40s; M=F
- A PNH clone is detectable in ~50% of aplastic anaemia at diagnosis and ~15-20% of low-risk MDS
- ~1/3 of PNH patients develop aplastic anaemia and vice versa - the same autoimmune process
Aetiopathogenesis
The molecular lesion
- PIGA is X-linked -> a single somatic hit in one HSC is enough (males and females equally affected)
- No GPI anchor -> loss of CD55 (DAF) and CD59 (MIRL), plus CD16, CD14, CD24, CD66b, alkaline phosphatase
| Protein | Normal role | Consequence of loss |
|---|---|---|
| CD55 | Accelerates decay of the C3 convertase | Unchecked C3 deposition -> opsonisation |
| CD59 | Blocks C9 polymerisation into the MAC | Intravascular lysis |
- The alternative pathway is constitutively active on all surfaces - normal cells are protected, PNH cells are not
Clonal expansion
- The PIGA mutation alone is not enough - immune selection pressure against GPI-anchored autoantigens spares the PNH clone
- This is why PNH and aplastic anaemia are the same disease process at different ends
Consequences of intravascular haemolysis
- Free plasma haemoglobin scavenges nitric oxide
- -> smooth muscle dystonia: abdominal pain, dysphagia/oesophageal spasm, erectile dysfunction, pulmonary hypertension, fatigue out of proportion to the anaemia
- Thrombosis - multifactorial: NO depletion, complement-activated platelets, free haemoglobin, impaired fibrinolysis (loss of GPI-anchored uPAR)
- Chronic urinary haemosiderin loss -> iron deficiency
Diagnosis
Suspect it
- Coombs-negative intravascular haemolysis with dec haptoglobin, inc LDH, haemoglobinuria
- Unexplained cytopenias, or aplastic anaemia
- Thrombosis at an unusual site, especially with haemolysis
- Unexplained iron deficiency with haemolysis; abdominal pain crises; recurrent dysphagia
Confirmation
- *High-sensitivity flow cytometry on peripheral blood* - the diagnostic test
- Loss of CD55 and CD59 on red cells -> Type I (normal), II (partial), III (complete deficiency)
- FLAER (fluorescent aerolysin, binds the GPI anchor) on granulocytes and monocytes - the granulocyte clone size is the accurate measure; red cell clone is underestimated by haemolysis and transfusion
- Ham's acid lysis test and the sucrose lysis test are obsolete
Also do
- Bone marrow aspirate + trephine + cytogenetics - to identify concurrent aplastic anaemia or MDS
- Iron studies, LDH, reticulocytes, haptoglobin, DAT (negative), renal function
Presentation differences
- Children rarely have haemoglobinuria - thrombosis (Budd-Chiari, splenic vein) and pain from NO-mediated vasoconstriction dominate
- Only ~25% report the classic dark morning urine
Management
A. Who to treat
- Complement inhibition for: significant haemolysis, transfusion dependence, thrombosis, or disabling NO-depletion symptoms
- *Subclinical/small clones with no haemolysis: monitor only*
B. Complement inhibitors
*The field has moved well beyond anti-C5 monotherapy. All four listed below are PBS/Life Saving Drugs Program funded in Australia*
| Agent | Target | Note |
|---|---|---|
| Ravulizumab | C5 | Preferred anti-C5 - 8-weekly IV vs eculizumab's 2-weekly |
| Eculizumab | C5 | The original; 2-weekly IV |
| Pegcetacoplan | C3 (proximal) | Subcutaneous. Superior to eculizumab where anaemia persists on C5 blockade |
| Iptacopan | Factor B (proximal) | Oral monotherapy - first of its kind |
| Danicopan | Factor D | Oral add-on to C5 inhibition for clinically significant extravascular haemolysis |
- Anti-C5 agents stop intravascular haemolysis but not C3 opsonisation (CD55 is still missing)
- -> residual extravascular haemolysis: persistent anaemia, reticulocytosis, normal LDH but positive C3d on DAT
- *This is the specific problem that proximal inhibitors (pegcetacoplan, iptacopan, danicopan) solve*
- All complement inhibition removes terminal complement -> catastrophic risk of encapsulated organism sepsis
- Meningococcal vaccination (ACWY + B) at least 2 weeks before starting, plus antibiotic prophylaxis (penicillin/ciprofloxacin) and a patient alert card
- Also pneumococcal and Hib vaccination
- Fever in a patient on a complement inhibitor is a medical emergency
- Breakthrough haemolysis on anti-C5 - infection, surgery, pregnancy, or poor responder polymorphisms (R885H, common in Japanese populations)
C. Supportive
- Folic acid (high red cell turnover)
- Iron replacement - urinary haemosiderin loss (expect a transient haemolytic exacerbation as new PNH red cells are produced)
- Transfusion as needed
- Corticosteroids - historical, poorly evidenced; avoid chronic use
D. Thrombosis
- Full anticoagulation for any thrombotic event, indefinitely
- Primary prophylaxis was historically used for large clones; effective complement inhibition markedly reduces thrombotic risk and has largely replaced it
- Complement inhibition should be started in anyone with PNH-related thrombosis
E. Curative
- Allogeneic HSCT is the only cure - reserved for concurrent severe aplastic anaemia, MDS/AML transformation, or failure of complement inhibition
- No longer justified for haemolysis alone
Associations
- Aplastic anaemia - bidirectional; a PNH clone predicts response to immunosuppression
- MDS - small PNH clones in low-risk disease predict a better prognosis and IST response
- Budd-Chiari syndrome - PNH is a classic cause; test every patient with hepatic vein thrombosis
- Cerebral venous sinus thrombosis, portal/mesenteric/splenic vein thrombosis, dermal vein thrombosis
- Pulmonary hypertension, CKD (chronic haemosiderin deposition and micro-infarction)
- Pregnancy - markedly increased thrombotic and maternal risk; specialist joint care
Natural history & complications
- Before complement inhibitors: median survival ~10-22 years, with thrombosis causing 40-67% of deaths
- With modern therapy: survival approaches that of the age-matched population
Prognostic drivers
- Granulocyte clone size - thrombotic risk rises sharply above ~50%
- Concurrent marrow failure
- Thrombotic history
Complications
- Thrombosis - the dominant cause of death untreated
- Chronic kidney disease from haemosiderin deposition
- Pulmonary hypertension
- Iron deficiency; aplastic crisis (parvovirus B19)
- Clonal evolution to MDS/AML in ~5%
- Spontaneous remission occurs in ~10-15% over decades as the clone contracts
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