Paroxysmal nocturnal hemoglobinuria (PNH)

Definition

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder of hematopoietic stem cells. Its hallmarks are complement-mediated intravascular hemolysis, a marked tendency to thrombosis and a variable degree of bone marrow failure. Despite the name, hemolysis occurs throughout the day and not only at night.

Classification

• Classic (hemolytic) PNH: hemolysis and thrombotic risk predominate; affects about one third of people with a PNH clone.
• PNH in the setting of bone marrow failure: mainly in acquired aplastic anemia; usually smaller, clinically silent clones (below 30 %). Here a PNH clone is regarded as a sign of immune-mediated marrow failure.
• Transitions are common: classic PNH can evolve from aplastic anemia and vice versa.

Occurrence & epidemiology

PNH is very rare: prevalence is estimated at up to 16 cases per million inhabitants and incidence at about 1.3 cases per million per year (data from the UK and France); it is probably underdiagnosed. The median age at onset is in the fourth decade, and both sexes are affected about equally. About half of people with acquired aplastic anemia have a detectable PNH clone at diagnosis.

Aetiopathogenesis

The cause is an acquired somatic mutation in the X-linked PIGA gene of a hematopoietic stem cell. As a result, the glycosylphosphatidylinositol (GPI) anchor cannot be formed and all GPI-anchored surface proteins are missing – including the complement regulators CD55 (DAF) and CD59 (MIRL). The affected red cells are defenceless against terminal complement activation and are destroyed intravascularly; CD59 plays the decisive role.

The released hemoglobin consumes nitric oxide (NO). NO depletion contributes to esophageal spasm, dysphagia, erectile dysfunction, pulmonary hypertension and kidney damage. Thrombophilia arises from complement activation, procoagulant microvesicles and NO depletion. Chronic urinary hemoglobin loss can lead to iron deficiency.

Clinical features

• Hemolysis: weakness, marked fatigue (in more than 80 %, often worse than the anemia would suggest), exertional dyspnea; only about a quarter report dark brown (morning) urine at diagnosis
• Hemolytic crises, triggered e.g. by infections, menstruation or other stressors: abdominal, chest, back, head and muscle pain
• Thrombosis as the most important complication: mainly venous and often at unusual sites (portal vein and other abdominal veins, hepatic veins, cerebral veins and venous sinuses, skin veins), less often arterial (myocardial infarction, stroke); abdominal and chest pain, dyspnea and hemoglobinuria can be warning signs
• Bone marrow failure: leukopenia and thrombocytopenia
• Kidneys: impaired function in about two thirds, due to hemosiderin deposits in the tubules and microthrombosis
• Smooth muscle: esophageal spasm, dysphagia, erectile dysfunction; pulmonary hypertension

Diagnosis

• Suspicion in unexplained normocytic Coombs-negative anemia with intravascular hemolysis, especially with leukopenia or thrombocytopenia, thrombosis at unusual sites or aplastic anemia
• Hemolysis markers: LDH markedly raised, haptoglobin low, indirect bilirubin and reticulocytes raised; hemoglobinuria during crises, hemosiderinuria constantly
• Flow cytometry (diagnostic standard, highly sensitive and specific): demonstration of absent GPI-anchored proteins (CD59, CD55) on red cells and of absent FLAER binding on leukocytes; determination of clone size
• Iron status because of possible urinary iron loss
• Bone marrow (not mandatory): usually erythroid hyperplasia; if aplastic anemia or myelodysplasia is suspected, including cytogenetics

Keep learning in the app

Further reading (open access)

1. MSD Manual Professional: Paroxysmal Nocturnal Hemoglobinuria (PNH)
2. Onkopedia-Leitlinie (DGHO): Paroxysmale nächtliche Hämoglobinurie (PNH)

Cross-references