Paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) has an unfortunate name. Its name implies that the main clinical feature is the presence of haemoglobin in the urine in the night, but this symptom isn’t present in everyone with PNH. Also, the name doesn’t explain the most important clinical features of the disease: Haemolysis, venous thrombosis, and pancytopaenia. It’s a rare disease.

Pathophysiology

All cells of the blood have a so-called membrane bound glycosylphosphatidylinositol (GPI) anchor. Many proteins are connected to this anchor, the most important being CD55 and CD59. The function of CD55 and CD59 is to act as a shield against complement-mediated haemolysis, protecting the blood cells, especially the RBCs, from getting destroyed. This anchor is encoded by the PIGA gene.

In PNH a haematopoietic stem cell acquires a mutation in PIGA, which causes them to lose the GPI anchor. As such they can’t express CD55 and CD59 either, making them susceptible to complement-mediated haemolysis. This mutated stem cell, and all the cells which will derive from it, are known as PNH clones. The RBCs derived from the PNH clone are not protected against complement-mediated haemolysis and are therefore constantly haemolysed.

The severity of the PNH depends on how much of the bone marrow is comprised of PNH clones. Many healthy people have some PNH clones in their bone marrow but are asymptomatic (subclinical PNH). However, if a person with a few PNH clones in their bone marrow develops aplastic anaemia the PNH clone will have more space to proliferate. As such there is a hypothesis that clinical PNH arises from the expansion of a PNH clone in an injured bone marrow.

Approximately half of all patients with PNH also have aplastic anaemia, and approximately half of all patients with aplastic anaemia have PNH.

Venous thrombosis and vasoconstriction are important features of PNH. The current hypothesis is that free haemoglobin produced by constant haemolysis scavenges and inactivates NO in the serum, and that free haemoglobin activates the endothelium. The loss of the potent vasodilator and the activation of the endothelium causes thrombosis.

Classification

We distinguish three types of PNH, based on the context under which it was diagnosed:

• Classic PNH – established PNH and symptoms but without another bone marrow disorder
• PNH in the setting of another bone marrow disorder – established PNH and symptoms and with aplastic anaemia, MDS, etc.
• Subclinical PNH – presence of PNH clones but without clinical symptoms

Clinical features

• Haemolytic anaemia
• Pancytopaenia – due to the high occurrence of simultaneous aplastic anaemia
• Venous thrombosis
  • Often in unusual locations, like hepatic, cerebral or abdominal veins
  • Can cause Budd-Chiari syndrome
• Abdominal pain
• Dark urine in the morning – due to increased haemolysis during the night and concentration of urine during the night
• Chronic kidney disease – due to chronic haemoglobinuria
• Pulmonary hypertension – due to vasoconstriction in the pulmonary circulation

Diagnosis and evaluation

• Laboratory
  • Haemolytic anaemia
  • Pancytopaenia
• Negative Coombs test (as the haemolysis is mediated by complement and not antibodies)
• Flow cytometry – absence of CD55 and CD59 on blood cells

Treatment

There are only two established therapies for PNH. The first is eculizumab, an anti-C5 antibody, which inhibits complement-mediated haemolysis. The second is allogenic stem cell transplantation.