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Paroxysmal nocturnal haemoglobinuria (PNH)

As an extremely rare autoimmune condition, PNH affects no more than a few people in every million. The symptoms of this blood disease include, but are not limited to, fatigue, brain fog, anaemia and thrombosis (blood clots).1,2

What is PNH?

PNH stands for paroxysmal nocturnal haemoglobinuria – an acquired, rare, chronic, potentially life-threatening blood disease commonly characterised by persistently low haemoglobin, thrombosis and debilitating symptoms. It occurs when the cells in the bone marrow responsible for making red blood cells (which help to carry oxygen around the body) mutate and produce defective blood cells.3 When this happens, the immune system is triggered to attack and destroy the red blood cells. The premature destruction of red blood cells is known as haemolysis. Red blood cells in a healthy individual last about 120 days before being broken down naturally in the body.4 People with PNH are subject to this premature destruction of red blood cells.5

Why is it called paroxysmal nocturnal haemoglobinuria?

The term PNH was coined in the early 20th century, based on a description of the symptoms observed in patients.

  • Paroxysmal refers to symptoms occurring intermittently or suddenly.
  • Nocturnal refers to the fact that it seems to occur at night (or to be observed first thing in the morning).
  • Haemoglobinuria refers to haemoglobin seen in urine (discolouring it dark red or black).

The term can be misleading for some people who have PNH because, in reality, the condition is present all the time and not everyone experiences dark urine.6

How rare is PNH?

It’s difficult to derive an exact figure for how many people have PNH because the numbers are extremely small, and an unknown number of individuals may be living with the condition undiagnosed. Some estimates put the proportion of people living with PNH at between 0.5 and 2 individuals per million of the general population, although recent studies suggest that the prevalence may be somewhat higher.7,8 By any estimate, it is a very rare disease. A person can develop PNH at any age, but the median age at diagnosis is during the 30s.9 Roughly equal numbers of males and females are affected. PNH is present throughout the world and among all ethnic groups. 

What are the symptoms of PNH?

Fatigue

Up to 96 per cent of people living with PNH experience fatigue.10

The symptoms of PNH can be different for different individuals. Some patients have PNH in a relatively mild form while others can experience severe, debilitating symptoms.11

Symptoms may include:12,13

  • Fatigue that interferes with everyday life
  • Brain fog
  • Anaemia
  • Back and abdominal pain
  • Severe headache
  • Thrombosis – blood clots
  • Haemoglobinuria – free haemoglobin, resembling blood, in urine.

Involuntary contractions of the smooth muscle in internal organs can cause further complications such as:

  • Dyspnoea – difficulty breathing
  • Dysphagia – difficulty swallowing
  • In men, erectile dysfunction.
Man with headphones.

How is PNH diagnosed?

It can take a long time to make a diagnosis of PNH as it is a very rare illness that many doctors will not be familiar with. Many of the symptoms of PNH are common to numerous other diseases; because of the wide range of symptoms they might have, PNH patients may initially be seen by a wide range of specialists (such as urologists, cardiologists and neurologists) before their condition is recognised as a blood and bone marrow problem so they can be referred to a haematologist.

Aplastic anaemia

Many individuals with PNH may simultaneously have another, closely related disorder known as acquired aplastic anaemia. Although the exact relationship between these disorders is unknown, researchers believe that PNH arises from autoimmune bone marrow failure, which is the cause of most cases of acquired aplastic anaemia.14

Initial diagnosis

PNH may be confirmed by a specific blood test, flow cytometry, which identifies PNH cells (blood cells that are missing specific proteins known as GPI-anchored proteins) and measures the proportion of PNH red blood cells within a patient’s blood.

Ongoing diagnosis

Doctors may recommend further flow cytometry testing to monitor progression. In addition, there are two other laboratory tests for monitoring the disease:

  • Lactate dehydrogenase (LDH). LDH is an enzyme present in red blood cells. This test gives an indication of how much haemolysis is going on in the patient’s body.
  • Complete blood count (CBC). The CBC indicates the counts of white blood cells, red blood cells and platelets, and the concentration of haemoglobin. In addition, it can help to identify bone marrow abnormalities.

What causes PNH?

Red blood cells, white blood cells and platelets are produced by stem cells in the bone marrow, a process called haematopoiesis. PNH occurs as a result of a defect in the mechanism for producing blood – specifically, a mutation in a gene of a stem cell in the bone marrow called the PIGA (or PIG-A) gene.15

PNH is an acquired genetic disorder

Paroxysmal nocturnal haemoglobinuria is caused by a somatic mutation, meaning a genetic alteration that occurs in a cell and is passed to the progeny of the mutated cell during cell division. So PNH is an acquired genetic disorder. It is not an inherited genetic alteration, but a somatic mutation in the PIG-A gene.16 As a somatic mutation, it cannot be passed on from parents to their children via sperm and eggs.17

In PNH, the abnormal stem cells make copies – or clones – of themselves, multiplying each time the cells divide. The abnormal cells mature into red blood cells that have mutant PIGA. These are called PNH red blood cells, or PNH clones. Problems arise when PNH clones meet the complement system.

Haemolysis

When red blood cells are broken up, the haemoglobin inside them is released. Haemoglobin is the red part of red blood cells that carries oxygen around the body. The release of haemoglobin into the plasma is what causes many of the symptoms of PNH.

There are two types of haemolysis, or two mechanisms: intravascular haemolysis (IVH) and extravascular haemolysis (EVH). Both occur after a cascade of activity has been started in the immune system’s complement system.18

  • IVH – when PNH red blood cells are destroyed inside the blood vessels.
  • EVH – when PNH red blood cells are destroyed in the liver and spleen.
Sobi explanation, types of haemolysis.

The complement system

The complement system, or complement cascade, is a group of about 60 proteins in the blood. These proteins are so called because they complement the work of white blood cells in fighting infections. They are always active at a low level. When abnormal cells – bacteria, viruses or other pathogens – are detected in the body, these proteins become more active, attacking and destroying the abnormal cells.

There are two key proteins relevant to PNH within the complement cascade, known as C3 and C5. These are activated in sequence as the immune system detects pathogens.

Sobi explanation, the complement system.

In response to the detection of a pathogen (or what is perceived to be a pathogen):

  • C3 is activated and splits (cleaves) into C3a and C3b
  • C3b activates C5
  • C5 splits into C5a and C5b
  • The membrane attack complex (MAC) is formed, working within the complement system to attack and destroy pathogens.

Normal red blood cells have a protective shield of proteins, known as GPI-anchored proteins, whose function is to prevent the complement system from attacking them. The gene that makes this protective shield is the PIGA gene.

PNH red blood cells, produced by stem cells with the PIGA gene deficiency, do not have this protective shield. As a result, the complement system proteins mistake PNH red blood cells for pathogens, and attack and destroy them. This is an autoimmune response, meaning that the body’s natural defence system fails to distinguish its own cells from foreign cells – resulting in premature or excessive destruction of red blood cells.

What treatments are available?

For many years, the only treatment options were blood transfusions, anticoagulants, steroids, iron therapy and folic acid.

There is only one possible cure for PNH and that is a bone marrow transplant. If successful, this procedure can permanently cure the patient of PNH. However, the risk associated with bone marrow transplant would often outweigh the likely benefits and it would therefore not be an option.

However, in the absence of a cure, treatments can allow people to live a life less impacted by the disease.

For many years, the only treatment options were blood transfusions, anticoagulants, steroids, iron therapy and folic acid.

C5 inhibitors (C5i)

In 2007, a therapeutic option called a C5 inhibitor (C5i) was made available to people living with PNH. A C5 inhibitor, as the name suggests, inhibits the production of the C5 protein within the complement cascade, preventing the inadvertent destruction of PNH red blood cells by C5. The introduction of C5 inhibitors led to a vast improvement at the time and increased life expectancy for PNH patients.24

C3 inhibitors (C3i)

C3 inhibitors (C3i), approved in 2021, are the newest class of treatment available for PNH. This new class of complement-inhibiting therapies works by targeting C3, which is upstream of C5 within the complement cascade. Targeting C3 controls both the C3-mediated EVH and the subsequent C5-controlled IVH. 

How can people living with PNH improve their lives?

Understanding the science behind PNH, symptoms and treatment can help someone living with PNH to gain insights about their health and care. They can take charge of their health by better understanding their symptoms and communicating their PNH-related goals with their healthcare team.

The limits imposed by PNH symptoms and care can make a person forget about the possibilities life can offer.25,26,27,28 Meetings with their care team can be a good opportunity to communicate ambitions for everyday life and goals for the future.

A support network may help people achieve those goals. Support can come from different corners of life and can include family, friends, patient advocacy groups or external resources

Discussions with the treating physician or involvement with patient advocacy groups can be an opportunity for new insights and support for patients wishing for change.

Haematology

The area of medicine dealing with diseases of the blood

1 Diagnosis and management of paroxysmal nocturnal hemoglobinuria Charles Parker et al
https://ashpublications.org/blood/article/106/12/3699/109767/Diagnosis-and-management-of-paroxysmal-nocturnal

2 Paroxysmal Nocturnal Hemoglobinuria, NORD
https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/

3 Hill A, DeZern AE, Kinoshita T & Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017;3:17028.

4 Frontiers in Physiology: How Do Red Blood Cells Die?
https://www.frontiersin.org/articles/10.3389/fphys.2021.655393/full

5 National Center for Biotechnology Information: Paroxysmal nocturnal hemoglobinuria (PNH), MedGen UID: 7471
https://www.ncbi.nlm.nih.gov/medgen/7471

6 PNH National Service, Leeds & London.
https://www.pnhleeds.co.uk/patients/what-is-pnh/

https://medlineplus.gov/genetics/condition/paroxysmal-nocturnal-hemoglobinuria/#frequency

8 https://pubmed.ncbi.nlm.nih.gov/34060690/

Paroxysmal Nocturnal Hemoglobinuria, NORD
https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/

10 Lima M. Laboratory studies for paroxysmal nocturnal hemoglobinuria, with emphasis on flow cytometry. Pract Lab Med 2020;20.

11 Lima M. Laboratory studies for paroxysmal nocturnal hemoglobinuria, with emphasis on flow cytometry. Pract Lab Med 2020;20.

12 Meyers G, Weitz I, Lamy T, et al. Disease-Related Symptoms Reported across a Broad Population of Patients with Paroxysmal Nocturnal Hemoglobinuria. Blood 2007;110:3683.

13 Mitchell R, Salkeld E, Chisolm S, et al. Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey. SM Clin Med Oncol 2017;1:1001.

14 Paroxysmal Nocturnal Hemoglobinuria, NORD
https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/

15 National Center for Biotechnology Information: Paroxysmal nocturnal hemoglobinuria (PNH), MedGen UID: 7471
https://www.ncbi.nlm.nih.gov/medgen/7471

16 https://pubmed.ncbi.nlm.nih.gov/8306954/

17 https://www.cancer.gov/publications/dictionaries/cancer-terms/def/somatic-mutation

18 Devos T, Meers S, Boeckx N et al., Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel. Eur J Haematol 2018;101:737-749.

19 Hill A, DeZern AE, Kinoshita T & Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017;3:17028.

20 Cho H. Complement regulation: physiology and disease relevance. Korean J Pediatr 2015;58:239–44.

21 Merle NS, Church SE, Fremeaux-Bacchi V & Roumenina LT. Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol 2015;6:262.

22 Hill et al. Nat Rev Dis Primers

23 Risitano et al. Front Immunol 2019

24 M Loschi et al. Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study
https://pubmed.ncbi.nlm.nih.gov/26689746/

25 Dingli D, Matos JE, Lebrhaunt K, et al. Clinical Burden of Paroxysmal Nocturnal Hemoglobinuria Among Patients Receiving C5 Inhibitors in the United States. Blood. 2020;136(Supplement 1).

26 Dingli D, Matos JE, Lebrhaunt K, et al. Work Productivity Loss and Quality of Life in Paroxysmal Nocturnal Hemoglobinuria Among Patients Receiving C5 Inhibitors in the United States. 2020;136(Supplement 1):3. 

27 Dingli D, Matos JE, Lehrhaupt K, et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey. Ann Hematol. 2022;101(2):251–263. 

28 Bektas et al. Paroxysmal nocturnal hemoglobinuria: patient journey and burden of disease. Manag Care Spec Pharm. 2020;26:S8-S14. 

NP-21226
Mar, 2022