Imagine a disease so rare that it touches only one in a million people, yet so aggressive that without modern treatment, it steals decades from a life typically diagnosed in young adulthood at a median age of 32.
Key Takeaways
- Paroxysmal nocturnal hemoglobinuria (PNH) has a prevalence of approximately 1-2 cases per million population worldwide.
- In the United States, the annual incidence of PNH is estimated at 0.13 per million individuals.
- PNH affects approximately 5-10 people per million in Europe according to population-based studies.
- PNH arises from somatic mutation in PIGA gene on X chromosome in hematopoietic stem cells.
- Deficiency of GPI-anchored proteins like CD55 and CD59 leads to complement-mediated lysis.
- Intravascular hemolysis in PNH is driven by C3 convertase stabilization due to CD55 loss.
- Dark urine upon waking reported in 60-70% of classical PNH patients.
- Fatigue is the most common symptom, affecting 80-90% of PNH patients.
- Abdominal pain occurs in 50-60% due to smooth muscle spasm from NO depletion.
- Flow cytometry shows PNH RBCs <1% sensitive for diagnosis.
- FLAER assay detects GPI deficiency on granulocytes with 99% sensitivity.
- LDH >3x ULN present in 95% of classical PNH.
- Eculizumab reduces LDH by 85-90% within 1 week of initiation.
- Ravulizumab every 8 weeks maintains LDH control in 96% of patients.
- Bone marrow transplant cures PNH in 70-80% matched sibling donors.
PNH is a rare blood disorder affecting mostly young adults, but treatments now dramatically improve survival.
Clinical Presentation
- Dark urine upon waking reported in 60-70% of classical PNH patients.
- Fatigue is the most common symptom, affecting 80-90% of PNH patients.
- Abdominal pain occurs in 50-60% due to smooth muscle spasm from NO depletion.
- Dysphagia and esophageal spasm reported in 25-35% of hemolytic patients.
- Thrombosis in unusual sites (hepatic vein, dermal) in 15-20% of cases.
- Anemia (Hb <10 g/dL) present in 70% at diagnosis.
- Headache occurs in 40% linked to pulmonary hypertension and NO scavenging.
- Bone marrow failure symptoms (pancytopenia) in 30-40% of patients.
- Renal impairment (GFR <60 mL/min) develops in 30-65% over time.
- Smooth muscle dystonias (erectile dysfunction in males 50%).
- Pulmonary hypertension detected in 35% by echocardiography.
- Jaundice intermittent in 20-30% during hemolytic crises.
- Back pain from renal hemosiderosis in 15-25% chronic cases.
- Infections secondary to neutropenia in 20% with BMF association.
- Leg ulcers rare but occur in 5-10% severe hemolytic patients.
- Impotence in 40-50% of male patients due to vasculopathy.
- Shortness of breath on exertion in 60% from anemia/PHTN.
- Budd-Chiari syndrome in 10-15% as presenting thrombosis.
- Pruritus after hemoglobinuria in 30% of episodes.
- Cognitive symptoms (confusion) from anemia in 10-15% severe cases.
- Pregnancy complications (fetal loss 20-30%) in PNH mothers.
- Splenomegaly absent in pure hemolytic PNH but present in 20% BMF.
- Chest pain from esophageal spasm in 20%.
- Chronic kidney disease stage 3+ in 50% untreated >10 years.
- Hemolytic crises triggered by infections in 40% of patients.
Clinical Presentation Interpretation
Paroxysmal Nocturnal Hemoglobinuria is essentially the body drafting a bleak internal memo that reads: "Waking up to port-wine urine is just the opening act for a relentless carnival of fatigue, pain, and rogue blood clots, sponsored by your own complement system."
Diagnosis
- Flow cytometry shows PNH RBCs <1% sensitive for diagnosis.
- FLAER assay detects GPI deficiency on granulocytes with 99% sensitivity.
- LDH >3x ULN present in 95% of classical PNH.
- Sucrose lysis test positive in 70-80% but nonspecific.
- Ham's acidified serum test specificity 95% but low sensitivity.
- Clone size measured by WBC GPI-AP loss >10% diagnostic.
- Reticulocyte count >3% and absolute reticulocyte count >100 x10^9/L.
- Haptoglobin undetectable in 90% during active hemolysis.
- Urinary iron loss 10-30 mg/day in hemolytic PNH.
- MRI detects renal cortical hemosiderosis in 65% chronic patients.
- Bone marrow biopsy shows erythroid hyperplasia in 80% hemolytic type.
- CD55/CD59 dual stain by flow cytometry gold standard (sensitivity 97%).
- PNH clone on monocytes >20% high risk for thrombosis.
- Bilirubin (unconj) 2-5x ULN in 85% classical cases.
- High-sensitivity FLAER detects clones as small as 0.01%.
- DAT negative in intravascular hemolysis distinguishing from AIHA.
- Serum EPO low despite anemia in 40% due to inappropriate response.
- Thrombocytopenia <100 x10^9/L in 30% at presentation.
- MRI T2* gradient echo for renal iron quantification.
- Leukocyte telomere length shortened in PNH with AA.
- Next-gen sequencing confirms PIGA mutations in 95% of clones.
- Absolute reticulocyte count >150 x10^9/L supports hemolytic PNH.
- Granulocyte clone size >50% predicts LDH >10x ULN.
Diagnosis Interpretation
To diagnose PNH, think of it as assembling a heretical mosaic: a tiny clone of treacherous, GPI-deficient blood cells throws a nonstop hemolytic party (with high LDH as the loud music), but you'll need the gold-standard flow cytometry to catch them red-handed, while also checking for their destructive side-effects like renal iron overload and a bone marrow working overtime to compensate.
Epidemiology
- Paroxysmal nocturnal hemoglobinuria (PNH) has a prevalence of approximately 1-2 cases per million population worldwide.
- In the United States, the annual incidence of PNH is estimated at 0.13 per million individuals.
- PNH affects approximately 5-10 people per million in Europe according to population-based studies.
- The median age at diagnosis of PNH is 32 years, with a range from 15 to 75 years.
- PNH shows no significant gender predilection, with a male-to-female ratio of approximately 1:1.
- In Japan, PNH incidence is reported as 0.075 per million per year based on national registries.
- Approximately 15-20% of PNH patients are diagnosed before the age of 20.
- PNH is more commonly associated with bone marrow failure syndromes in 40-50% of cases.
- Global prevalence estimates suggest around 8,000-10,000 patients worldwide.
- In a French cohort, PNH prevalence was 1.3 per million.
- PNH clonal size >50% GPI-deficient granulocytes correlates with hemolytic phenotype in 70% of cases.
- Median survival for classical PNH is 10-15 years from diagnosis without treatment.
- Thrombotic events occur in 30-40% of untreated PNH patients.
- Bone marrow failure precedes PNH diagnosis in about 25% of patients.
- PNH type III cells (complete GPI deficiency) are found in 90% of hemolytic cases.
- Annual incidence in children under 18 is less than 0.05 per million.
- In AA Asia, PNH is underdiagnosed with prevalence <1 per million.
- 50-60% of PNH patients have subclinical disease with small clones.
- Median time from symptom onset to PNH diagnosis is 1-2 years.
- PNH is present in 20-30% of patients with aplastic anemia.
- Prevalence of PNH clones >1% in general population is 0.02%.
- In a UK registry, 150 new PNH cases were identified over 10 years.
- Female patients represent 52% of diagnosed PNH cases in US registries.
- PNH incidence peaks in the 30-40 age group at 0.2 per million.
- 10% of PNH patients develop myelodysplastic syndrome over 10 years.
- Historical data shows 25% mortality within 5 years pre-eculizumab.
- PNH in pregnant women occurs in 5-10% of female patients aged 20-40.
- Sub-Saharan Africa reports higher PNH rates linked to infections at 2 per million.
- 35% of PNH patients have coexisting autoimmune disorders.
- Median diagnostic delay in resource-poor settings is 3-5 years.
Epidemiology Interpretation
Despite its astonishing rarity, PNH is a master of cruel arithmetic, striking individuals in the prime of life and wielding a delayed diagnosis, a ticking clock on survival, and a high risk of devastating clots as its primary weapons.
Pathophysiology
- PNH arises from somatic mutation in PIGA gene on X chromosome in hematopoietic stem cells.
- Deficiency of GPI-anchored proteins like CD55 and CD59 leads to complement-mediated lysis.
- Intravascular hemolysis in PNH is driven by C3 convertase stabilization due to CD55 loss.
- Thrombophilia in PNH results from platelet activation and free hemoglobin scavenging NO.
- PIGA mutation rate is estimated at 10^-6 per hematopoietic stem cell division.
- Type I PNH cells have partial GPI deficiency (10-20% normal levels).
- CD59 loss increases MAC formation by 50-100 fold in PNH erythrocytes.
- Nocturnal exacerbation linked to mild respiratory acidosis increasing C3 saturation.
- Bone marrow failure in PNH associated with immune attack on GPI-deficient clones.
- Free hemoglobin induces hypertension via NO depletion in 60% of hemolytic patients.
- Lactate dehydrogenase (LDH) elevation >10x ULN in 80% classical PNH.
- Complement activation generates anaphylatoxins C3a/C5a promoting inflammation.
- PNH clones expand due to type I interferon hypersensitivity of mutant HSCs.
- Urinary haemosiderin present in 90% of patients with ongoing hemolysis.
- Reduced CD55/CD59 on granulocytes predicts thrombosis risk (clone size >60%).
- Erythrocyte membrane stress from complement leads to 1-2% daily RBC destruction.
- PIGA mutations are hypomorphic, allowing clonal dominance without apoptosis.
- Macrophage activation by hemolysis contributes to bone marrow fibrosis in 20%.
- C5 inhibition reduces hemolysis by 90% but residual extravascular hemolysis occurs.
- GPI-AP loss affects 20+ proteins including urokinase receptor linked to thrombosis.
- Hemoglobinuria episodes average 3-5 per week in untreated classical PNH.
- Nitric oxide scavenging by Hb causes smooth muscle dystonia and dysphagia.
- PNH HSCs evade immune surveillance via reduced CD55/CD59 signaling.
- Reticulocyte count elevated >10% in 70% due to compensatory erythropoiesis.
Pathophysiology Interpretation
In this cellular coup, a crafty mutation on the X chromosome disarms the blood factory's security system, leaving red cells defenseless against complement's friendly fire, turning the bloodstream into a chaotic battlefield of exploding cells, sticky clots, and stolen nitric oxide.
Prognosis
- 5-year survival >95% with C5 inhibitors vs 65% untreated.
- Thrombosis risk reduced 87% with eculizumab (0.62 vs 7.43 events/100 pt-yrs).
- Renal failure progression halted in 70% on terminal complement inhibitors.
- Median survival >25 years with modern anti-C5 therapy.
- Cumulative thrombosis incidence 40% at 10 years untreated.
- Post-BMT relapse of PNH clone <5% with myeloablative conditioning.
- LDH control >90% correlates with 80% transfusion independence.
- 10-year OS 97% in ravulizumab switchers from eculizumab.
- Aplastic anemia evolution in subclinical PNH 15-20% over 5 years.
- Pregnancy success rate 67% with complement inhibition.
- Pulmonary HTN regresses in 50% after sustained LDH control.
- AML transformation risk 2-5% lifetime in classical PNH.
- Fatigue resolution in 75% achieving Hb >10 g/dL.
- ESRD incidence <5% with early complement blockade.
- Clone size stability in 60% on long-term C5i without expansion.
- Survival benefit NNT=3 for eculizumab vs supportive care.
- Thrombotic mortality reduced from 22% to 1% post-eculizumab.
- Renal recovery (eGFR improvement) in 33% after 2 years therapy.
Prognosis Interpretation
The modern treatment of PNH has been utterly transformed, turning a once dire and unpredictable blood disorder into a manageable chronic condition where patients can confidently expect to live a full life, free from the once-certain specters of clots, kidney failure, and early death.
Treatment
- Eculizumab reduces LDH by 85-90% within 1 week of initiation.
- Ravulizumab every 8 weeks maintains LDH control in 96% of patients.
- Bone marrow transplant cures PNH in 70-80% matched sibling donors.
- Pegcetacoplan reduces transfusion dependence by 85% in phase 3 trials.
- Folic acid supplementation recommended at 5 mg daily for all hemolytic patients.
- Iron chelation with deferasirox for serum ferritin >500 ng/mL.
- Anticoagulation with warfarin for thrombosis history (target INR 2-3).
- Iptacopan (C3 inhibitor) normalizes Hb in 80% without transfusions.
- Immunosuppression with ATG/cyclosporine for PNH with AA in 60% response.
- Vaccinations (meningococcal, pneumococcal) mandatory pre-C5i >90% compliance.
- Crovalimab subcutaneous C5i sustains LDH <1.5x ULN in 85%.
- RBC transfusions average 4-6 units/year pre-treatment reduced to 0.5 post-C5i.
- Prophylactic anticoagulation in high-risk (clone >50%) reduces events by 80%.
- Danicopan add-on triples proximal C3 inhibition efficacy.
- HSCT 5-year survival 80% in pediatric PNH.
- Eculizumab breakthrough hemolysis in 10% managed with 600mg dose.
- Renal function stabilizes (eGFR +5 mL/min) after 1 year C5 inhibition.
- Anti-C5 antibody development <1% with long-term eculizumab.
- Eltrombopag response in thrombocytopenic PNH 40-50%.
- Meningococcal prophylaxis with antibiotics lifelong in C5i users.
- Survival post-BMT 90% if no prior thrombosis.
- LDH normalization (<1.5x ULN) breakthrough threshold for rescue dosing.
- Quality of life (FACIT-F) improves by 10 points post-eculizumab.
Treatment Interpretation
While eculizumab kicks hemolysis to the curb within a week, and newer C5 inhibitors like crovalimab and iptacopan offer convenient, potent control, the real strategic depth of PNH management lies in a multi-pronged artillery: mandatory vaccinations, vigilant anticoagulation, and add-ons like danicopan, all supporting the fact that while targeted C5 inhibition is the frontline marvel, the true cure—and its significant risks—still belongs to the old guard of bone marrow transplant.