Paroxysmal Nocturnal Haemoglobinuria
Acquired clonal stem cell disorder caused by PIGA gene mutation, resulting in GPI-anchor deficient blood cells susceptible to complement-mediated haemolysis. Characterised by haemolytic anaemia, thrombosis, and bone marrow failure.
Key Facts
Acquired clonal disorder: somatic mutation in PIGA gene → deficiency of GPI-anchored proteins (CD55/DAF and CD59/MIRL) on blood cells Classic triad: haemolytic anaemia + thrombosis + cytopenias (bone marrow failure) Complement-mediated intravascular haemolysis: uncontrolled complement activation on GPI-deficient RBCs Morning haemoglobinuria: dark urine on waking (classically described but not always present; nocturnal complement activation) Thrombosis: most feared complication and leading cause of death; hepatic vein (Budd-Chiari), cerebral, portal; unusual sites Flow cytometry: diagnostic — demonstrates loss of GPI-anchored proteins (CD55, CD59) on RBCs, granulocytes, monocytes Eculizumab/ravulizumab: anti-C5 complement inhibitor; transforms prognosis (NICE TA698) Association with aplastic anaemia: ~30% of aplastic anaemia patients develop PNH clone
Overview
Key Facts
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired clonal haematopoietic stem cell disorder characterised by complement-mediated haemolysis, thrombosis, and bone marrow failure.
Epidemiology
- Rare: incidence ~1–2 per million per year
- Peak onset: 30–50 years; equal sex distribution
- ~30% of aplastic anaemia patients develop PNH clone
Aetiology
- Somatic mutation in PIGA gene (X-linked) in haematopoietic stem cell
- PIGA encodes enzyme required for GPI-anchor biosynthesis
Pathophysiology
- GPI-anchor deficiency → loss of complement regulatory proteins from cell surface:
- CD55 (DAF): inhibits C3 convertase
- CD59 (MIRL): inhibits membrane attack complex (MAC)
- Without CD55/CD59: uncontrolled complement activation on RBC surface → MAC insertion → intravascular haemolysis
- Nocturnal: mild respiratory acidosis during sleep → complement activation
- Free haemoglobin → nitric oxide scavenging → smooth muscle dystonia → dysphagia, erectile dysfunction, abdominal pain
- Thrombosis: complement activation on platelet surface + free Hb + nitric oxide depletion
Clinical Presentation
Haemolytic Anaemia
- Chronic haemolysis with intermittent exacerbations
- Dark urine (haemoglobinuria) — classically morning; may be throughout day
- Fatigue (often severe and disproportionate to Hb level)
- Jaundice
Thrombosis (Leading Cause of Death)
- Budd-Chiari syndrome (hepatic vein thrombosis)
- Cerebral venous sinus thrombosis
- Portal/mesenteric vein thrombosis
- DVT/PE
- Unusual sites (dermal veins → skin necrosis)
Bone Marrow Failure
- Cytopenias: anaemia, neutropenia, thrombocytopenia
- May present as or evolve from aplastic anaemia
Smooth Muscle Dystonia (NO depletion)
- Dysphagia, abdominal pain, erectile dysfunction
Red Flags
- Coombs-negative haemolytic anaemia with thrombosis (classic PNH)
- Thrombosis at unusual sites (Budd-Chiari in young patient)
- Cytopenias with haemolysis (aplastic anaemia-PNH overlap)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| AIHA | DAT positive, spherocytes | DAT |
| Aplastic anaemia | Pancytopenia, hypocellular marrow, no haemolysis | Bone marrow biopsy |
| TTP/HUS | MAHA, schistocytes, renal/neuro features | ADAMTS13 |
| Myelodysplasia | Elderly, dysplastic cells, macrocytic | Bone marrow |
| Budd-Chiari (other causes) | Hepatic vein thrombosis, hepatomegaly, ascites | Imaging, thrombophilia screen |
Diagnosis / Investigation
Bloods
- FBC: anaemia, ± neutropenia, ± thrombocytopenia
- Reticulocyte count: raised
- LDH: markedly raised (intravascular haemolysis)
- Haptoglobin: undetectable
- Bilirubin (unconjugated): raised
- DAT: NEGATIVE (not antibody-mediated)
- Urinalysis: haemoglobinuria, haemosiderinuria
Definitive Diagnosis
- Flow cytometry: GOLD STANDARD — demonstrates absence/reduction of GPI-anchored proteins (CD55, CD59, FLAER) on RBCs, granulocytes, and monocytes
- Quantifies PNH clone size
Other
- Bone marrow biopsy: if aplastic anaemia suspected (hypocellular marrow)
- Imaging: if thrombosis suspected (Doppler, CT, MRI)
Management
Pharmacological
Complement inhibitors (transform prognosis):
- Eculizumab 900mg IV every 2 weeks (after loading) — anti-C5 monoclonal antibody; prevents MAC formation (NICE TA698)
- Ravulizumab: long-acting anti-C5; every 8 weeks (improved convenience)
- Iptacopan, danicopan, pegcetacoplan: newer complement inhibitors targeting C3/factor B; address extravascular haemolysis
CRITICAL: meningococcal vaccination BEFORE starting eculizumab/ravulizumab (C5 blockade → increased meningococcal infection risk)
- MenACWY + MenB vaccines; consider ciprofloxacin prophylaxis
Anticoagulation:
- Warfarin for treatment/prevention of thrombosis (role reduced with complement inhibitors)
Supportive:
- Folic acid 5mg daily
- Iron supplementation (iron lost in haemoglobinuria)
- Transfusion PRN
- EPO if suboptimal erythropoiesis
Curative
- Allogeneic stem cell transplant: only cure; reserved for severe/refractory cases or progressive bone marrow failure
Referral Criteria
- Specialist PNH centre: all confirmed PNH (UK National PNH Service)
- Haematology: urgent for suspected PNH
Prognosis
- Pre-eculizumab median survival: ~10–15 years; thrombosis was leading cause of death (~40–60% of deaths)
- Post-eculizumab: near-normal life expectancy for many patients
- Eculizumab: reduces haemolysis, thrombosis risk, transfusion dependence, and fatigue
- ~15% may undergo spontaneous remission
- ~5% transform to MDS or AML
- Quality of life: significantly improved with complement inhibitors
Other Relevant Information
PNH vs AIHA Comparison
| Feature | PNH | Warm AIHA |
|---|---|---|
| DAT | Negative | Positive |
| Mechanism | Complement (no antibody on RBC) | IgG autoantibody |
| Haemolysis | Intravascular | Extravascular |
| Thrombosis | Major feature | Not prominent |
| Treatment | Eculizumab | Prednisolone |