Definition and epidemiology

Extract from the VADE-MECUM by Professor Gérard Socié 

A rare, acquired, chronic clonal disease

Paroxysmal nocturnal haemoglobinuria (PNH), also known as Marchiafava-Micheli syndrome, is a disease related to clonal expansion of one or more hematopoietic stem cells that have acquired a somatic mutation of the PIG-A (phosphatidylinositol glycan class A) gene 1, 2.

Located on the X chromosome, this gene is involved in the synthesis of glycosylphosphatidylinositol (GPI). GPI acts as an anchor for many membrane proteins, two of which, CD55 and CD59, are essential for protecting blood cells from the lytic activity of the complement2.

This gene’s mutation prevents or limits the normal synthesis of the GPI anchor. This results in a partial or total CD55 and CD59 deficiency on the surface of blood cells: leukocytes, platelets and particularly erythrocytes. The latter then have an abnormal sensitivity to the lytic activity of the complement responsible for the intravascular haemolysis characteristic of the disease.1 2.

PNH may occur on its own, but also frequently in the context of myelosuppression such as bone marrow failure2, 3.

PNH is chronic and progressive, and can be fatal2.

PNH is a rare disease with a prevalence of 16 cases/1 million4. The prevalence is similar in men and women5.

A population of young adults

Patients with PNH are mainly young adults. The median age at diagnosis is 33 (6-82 years)6.

The median survival time according to the different studies is 10 to 22 years after diagnosis5, 6, 7.

Kaplan-Meier curve showing survival after PNH was diagnosed

in 454 patients in the French Haematology Society’s registry5

Survival after 10 years 75+-3%
 

In the French Haematology Society (SFH) registry of 454 patients between 1950 and 2005, 25% of PNH patients died within 10 years5.

Thrombosis is the leading cause of death: 40-67% of deaths are due to thrombotic complications of the disease. The most common thrombosis sites are venous: the hepatic veins (Budd-Chiari syndrome), cerebral veins, mesenteric veins, renal veins7, 8

PNH in children

PNH can occur in children. The clinical picture is no different from that of PNH in adults, combining signs of haemolysis, myelosuppression and thromboembolic events1.

The PNH men2, 9, 10 In 1866, Sir William Gull gave the first clearly detailed clinical description of PNH. He described “intermittent haematuria” in an anaemic patient. In 1882, Dr Paul Strübing recognized the pigment in urine as haemoglobin and referred to this event as paroxysmal haemoglobinuria. This disease was then forgotten until Marchiafava reported a case in Italy 29 years later. In 1931, Micheli published further information and used the term “splenomegalic haemolytic anaemia with haemoglobinuria and haemosiderinuria, Marchiafava Micheli-type”, hence the name Marchiafava-Micheli syndrome. In the early twentieth century, Van der Bergh demonstrated that in patients with PNH the RBCs became lysed in the presence of acidified serum, and suspected that the complement was responsible for this abnormal lysis. In 1944, Sir John Dacie noted the possible association with aplasia and suggested that PNH was a clonal disease affecting hematopoietic stem cells. We now know that the term “PNH” does not describe the disease correctly. In reality, it is chronic intravascular haemolysis, which can be manifested, but not exclusively, by haemoglobinuria (see Chapter 3 “Semiotics”).

Summary

• PNH is rare chronic and progressive disease that can be fatal.
• PNH affects mainly young adults.
• Thrombosis is the leading cause of death.