Paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH), also known as Marchiafava-Micheli syndrome or Strübing-Marchiafava anaemia, is an acquired haematopoietic stem cell disorder whereby some of the red blood cells produced are defective and are susceptible to premature destruction by the immune system, leading to complement-mediated haemolysis and haemoglobinuria.

Terminology

The term comes from a mistaken 19^th century belief that the haemolysis and subsequent haemoglobinuria occurred only intermittently (paroxysmally) and with greater frequency during the night (nocturnal). Haemoglobinuria is most prominent in the morning after the urine has concentrated overnight during sleep but haemolysis in paroxysmal nocturnal haemoglobinuria is actually a constant process.

Epidemiology

Prevalence is low, at 1-10 per 1,000,000. No difference in prevalence between the sexes has been found, M:F = 1:1. Median age at diagnosis is in the fourth decade ².

Clinical presentation

• haemolytic anaemia

  • profound fatigue

  • exertional dyspnoea

• haemoglobinuria

• dysphagia

• abdominal pain

• erectile dysfunction

Complications

Common

• thrombosis

• renal impairment

• pulmonary hypertension

Rare

• bone marrow failure

• myelodysplasia

• acute leukaemia

• renal haemosiderosis

• avascular necrosis of the hip

Pathology

Paroxysmal nocturnal haemoglobinuria is caused by a defect in surface proteins of red blood cells, typically due to an acquired mutation in the PIGA gene on the X chromosome in a haematopoietic stem cell ^1,7. These surface proteins usually protect red blood cells and other immune cells from destruction via the complement system, thus a defect in these proteins increases their destruction, leading to the aforementioned clinical presentation ¹.

In addition to the anaemia from haemolysis, patients suffer from the direct effects of intravascular haemolysis that results in the absorption of nitric oxide, a key molecule in homoeostasis, leading to smooth muscle dysfunction and platelet activation, markedly raising the risk of thrombosis ¹.

Radiographic features

Ultrasound, CTA and MRI/MRA may show features of thrombosis of major vessels, particularly in the abdomen. Rarely thrombosis of smaller vessels may cause osteonecrosis of the femoral head.

MRI of the abdomen shows renal haemosiderosis.

Treatment and prognosis

Management options include:

• blood transfusions

• anticoagulation

• haematopoetic stem cell transplant ¹

• eculizumab ¹

  • has been shown to prevent most of the complications and significantly improves survival ^2,5,6

Without therapy approximately 50% of patients die as a direct result of the disease. Many others are transfusion dependent for decades ³. Pregnancy results in extremely high risk for maternal and fetal mortality, predominantly resulting from thrombotic complications ⁴.

History and etymology

The condition was first described by German physician Paul Strübing in 1882, with further descriptions made by Italian physicians Ettore Marchiafava (1847-1935) and Ferdinando Micheli (1872-1936) ⁸.