Paroxysmal nocturnal haemoglobinuria

PNH is often undiagnosed, say Dr Tharani Balasubramaniam, Dr Richard Kelly, Dr Anita Hill and Professor Peter Hillmen.

The classical symptom seen in PNH is haemoglobinuria (black urine) (Photograph: Professor P Hillmen)
The classical symptom seen in PNH is haemoglobinuria (black urine) (Photograph: Professor P Hillmen)

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare bone marrow disorder in which abnormal blood cells are produced that are susceptible to attack by complement.

Complement has a role in clearing pathogens from the body, but it does not normally attack the body's own cells due to complement regulatory proteins on cell surfaces and in the circulation.

Patients with PNH lack specific complement regulatory proteins (CD55 and CD59) on their cell surface. Lack of these specific proteins on red blood cells makes them prone to destruction in the circulation (intravascular haemolysis).

This haemolysis results in release of free haemoglobin into the bloodstream causing many of the symptoms and complications of the disease.

In view of the rarity of PNH, the disease incidence is not well defined. The most reliable data come from work undertaken in Yorkshire,1 which shows the prevalence of patients with PNH blood cells is 15.9 per million and the incidence is 1.3 per million of the total population.

PNH can develop at any age but most patients are diagnosed in their thirties. It is an acquired disorder rather than an inherited one, and can present de novo or in patients with a history of aplastic anaemia.

Patients with PNH are commonly either misdiagnosed or undiagnosed for long periods because presenting symptoms can be non-specific in nature.

The classic symptom seen in PNH is haemoglobinuria (black urine) due to the presence of free haemoglobin. However, it is not present in all patients with PNH and may be confused with haematuria. Other commonly observed symptoms include dysphagia, abdominal pain, severe lethargy, reduced quality of life, erectile dysfunction and, in the long term, the development of pulmonary hypertension, renal impairment and an increased tendency to develop thrombosis.

The most common cause of death in PNH is thrombosis, occurring in approximately 40% of patients. These thromboses predominantly occur in the venous system in typical sites, such as deep limb veins, with consequent pulmonary emboli, but characteristically also at atypical sites, such as the hepatic, mesenteric and cerebral veins.

The risk of arterial thrombosis is also elevated, with increased occurrences of MI and stroke.

Patients with the following should be referred to a haematologist for further evaluation including testing for PNH (which is done by flow cytometry):

1. Haemoglobinuria or evidence of intravascular haemolysis with raised serum LDH levels and reduced serum haptoglobin levels.

2. A thrombosis in an unusual site, such as the liver, mesenteric or cerebral veins.

3. Aplastic anaemia or unexplained cytopenias.

Until recently, management of PNH patients was mainly supportive in nature with blood transfusions and anticoagulation in selected patients. Some patients are iron deficient due to persistent loss of red blood cells from haemoglobinuria and require oral iron supplements. Untreated, the median survival is approximately 10 to 22 years.

Allogeneic bone marrow transplantation is the only curative option but this carries a substantial risk of death and of long-term complications.

Eculizumab is a new therapy which was licensed by the European Medicines Agency in June 2007 for the treatment of PNH. It is a monoclonal antibody that prevents the formation of the terminal components of complement and it thereby prevents the destruction of PNH red blood cells.

There have been three clinical trials in the use of eculizumab in PNH with remarkable results. Most patients treated either no longer require blood transfusions or have a significant reduction in the number of transfusions. Eculizumab also protects against thrombosis and renal impairment and patients report dramatic improvements in their quality of life.

Eculizumab may be given as an IV infusion every two weeks. This provides flexibility to patients, impacts less on their daily lives and may allow a return to full-time employment. Infusion related reactions are rare but transient headaches may occur with the first two to three infusions.

Key Points
  • PNH is an acquired haemolytic anaemia often with severe symptoms.
  • It is associated with a high risk of thrombosis (particularly hepatic and cerebral veins).
  • Severely affected patients are treated with anti-complement therapy (eculizumab).
  • Consider meningococcal infection if a patient on eculizumab is acutely unwell.

Meningococcal infection
There is an increased risk of infection with Neisseria meningitidis in patients on eculizumab, because this bacterium requires terminal complement for clearance. Patients are given prophylactic penicillin V (500mg twice daily), carry an alert card and are also vaccinated against meningococcal disease.

Patients who become unwell and have a raised temperature are advised to seek urgent medical advice to rule out N meningitidis septicaemia.

Patients often do not present with the typical meningitis features and therefore it is important to keep this diagnosis in mind.

The patients have contact numbers for direct access to the PNH service, including 24-hour specialist medical cover.

Specialist services
NHS specialised services oversee equality of access to highly specialised services in England. In April 2009, a new national service for PNH was set up to provide expertise in the management of this disease via two specialist centres, St James's Hospital in Leeds and King's College Hospital in London.

Patients with a diagnosis of PNH from across the UK are seen either at these centres or at outreach clinics in different regions of the country. Patients are referred through their local haematologist and the PNH service works with the local centre to provide patients with the understanding, treatment and support that is needed in this rare debilitating condition.

  • Dr Balasubramaniam is a specialist registrar and Dr Kelly, Dr Hill and Professor Hillmen are consultant haematologists, St James's University Hospital, Leeds
1. Hill A, Platts PJ, Smith A et al. The incidence and prevalence of paroxysmal nocturnal haemoglobinuria (PNH) and survival of patients in Yorkshire. (Abstract). Blood 2006; 108(11): 290 a. Abstract 985.

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