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OVERVIEW AND PATHOPHYSIOLOGY OF PNH

The medical information provided on this website is by way of general guidance only. You should always contact your clinician for medical advice and do not rely upon the information provided here.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired genetic disease, so it cannot be inherited and can’t be passed down to children. It occurs in both men and women at different ages, and patients are usually diagnosed in young adulthood. Considered a bone marrow disorder, about 3.5* to 5.7 † new cases of PNH are diagnosed per million people each year, and 13† to 38* people per million are living with it.

People with PNH can experience a wide range of symptoms. Common ones include fatigue, difficulty swallowing (dysphagia), shortness of breath (dyspnoea), anaemia (low red blood cell levels), yellowing of the skin and eyes (jaundice), abdominal pain, erectile dysfunction (in men) and dark or red urine (haemoglobinuria), especially in the morning. Difficulty swallowing, abdominal pain and erectile dysfunction are caused by problems with smooth muscle movement caused by PNH.

PNH is caused by a genetic change or mutation in the PIG-A gene. This mutation leads to blood cells missing important GPI-anchored proteins. These proteins usually protect blood cells from being attacked by the body’s immune system. With fewer of these proteins (or a complete absence of them), red blood cells are destroyed by the complement part of the immune system in a process called haemolysis, which causes many of the symptoms of PNH.

PNH can also cause serious complications such as blood clots, which can lead to strokes or other life-threatening conditions. A study of people with PNH (co-authored by PNH patients) found that patients also report symptoms like anxiety, loss of appetite, and chest pain, highlighting how PNH can affect each person in different ways.

Though PNH is a serious condition, treatments have improved significantly over recent years. Currently the only cure is a bone marrow transplant however PNH specific treatments can reduce symptoms, improve quality of life and help prevent serious complications. However these treatments are not available to all patients in all countries due to their high cost.

Anchor for Diagnosis

DIAGNOSIS

Diagnosing paroxysmal nocturnal haemoglobinuria (PNH) can take a long time, sometimes months or even years, because it is rare, and its symptoms often look like other common conditions. Doctors may not think of PNH at first when patients experience symptoms like anaemia, abdominal pain, fatigue or trouble swallowing, which can lead to misdiagnosis.

However, PNH should be considered in patients with unexplained blood clots, especially in unusual locations, or those showing signs of red blood cell destruction (haemolysis).

Important signs that should lead to testing for PNH include:

  • Unexplained blood clots, particularly in unusual places like deep veins i.e. around the liver (Budd-Chiari syndrome).
  • Bone marrow disorders like aplastic anaemia (AA) or myelodysplastic syndrome (MDS).
  • Anaemia where the body attacks its own red blood cells (Coombs-negative haemolytic anaemia).
  • Symptoms like fatigue, abdominal pain, difficulty swallowing, dark urine and erectile dysfunction.

The gold standard test for diagnosing PNH is flow cytometry. It is the most precise technique to provide the most accurate identification of PNH:

  • Measure the number of PNH-affected blood cells.
  • Detect blood cells missing protective proteins.

Other tests may include:

  • Full blood count to check blood cell levels (including reticulocytes)
  • Lactate dehydrogenase (LDH) levels to see how much red blood cell destruction is happening.
  • Kidney function tests, since PNH can affect kidney health.
  • Ferritin and bilirubin levels to track iron loss and red blood cell breakdown.

In some cases, a bone marrow biopsy may be needed to assess the status of the bone marrow. Early diagnosis and regular check-ups are crucial to managing PNH and avoiding complications.

Anchor for Symptoms

SYMPTOMS

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare blood disorder with a wide range of symptoms, which can vary significantly between patients. Some people may experience severe symptoms, while others have mild or no symptoms at all.

The condition primarily affects red blood cells, causing them to break down (haemoloysis), but this can also lead to other complications throughout the body. The symptoms of PNH are caused by the destruction of red blood cells (haemolysis) and the impact this has on various organs and systems.

Commonly recognised symptoms of PNH:

  • Fatigue: This is one of the most common symptoms of PNH and may be a symptom of anaemia. However, fatigue can also occur independently of anaemia. In PNH, fatigue experienced by a person is often much worse than would be expected in people with other types of anaemia. Patients report that fatigue can present in a variety of ways including listlessness, heaviness in limbs, problems sleeping and can also impact other things e.g. cognitive problems like trouble concentrating or memory.
  • Anaemia: This happens when the body doesn’t have enough red blood cells due to haemolysis. It can cause weakness, dizziness, and pale skin.
  • Dark brown to red- or orange-coloured urine (haemoglobinuria): As red blood cells break down, ‘free haemoglobin’ is released into the plasma (bloodstream) and is eventually excreted in urine, causing a dark or reddish tint. It can occur any time of day.
  • Abdominal pain (smooth muscle dystonia): When PNH red blood cells are destroyed (haemolysis) their contents, particularly the haemoglobin, are released into the circulation. Haemoglobin binds to nitric oxide, (used by the body to help the muscles of the intestine (amongst other muscles) to work properly). Free haemoglobin in the bloodstream results in a low level of nitric oxide, and leads to spasms in the muscles of the intestines causing abdominal pain.
  • Jaundice: Bilirubin, which is a breakdown product of haemoglobin usually processed by the liver. When the level of haemolysis is very high, the liver has difficulty processing the bilirubin quickly enough, leading to jaundice causing a yellowing of the skin and eyes.
  • Difficulty swallowing (dysphagia): Smooth muscle dysfunction can make it hard to swallow, leading to discomfort or weight loss. Free haemoglobin in the bloodstream results in a low level of nitric oxide and can also affect the oesophagus (gullet) causing difficulty swallowing
  • Shortness of breath (dyspnoea): A result of low red blood cell levels and reduced oxygen in the body, causing difficulty breathing, especially during physical activity. It can also be experienced due to increased blood pressure in the lungs (pulmonary hypertension) that may occur in PNH.
  • Blood clots (thrombosis): There is a very high risk of PNH leading to the formation of dangerous blood clots, which can occur anywhere including unusual places like the veins of the liver, around the brain or other parts of the body. The symptoms of thrombosis vary and depend largely on where they develop and their size.

Each person with PNH may experience these symptoms differently, and their symptoms can change over time. Early recognition and treatment can help manage the condition more effectively. It is important to note that patients are reporting a wider set of symptoms than those listed above which they believe are linked to PNH.

A collaborative research study undertaken with patients identified symptoms including joint pain, bloating and sensitivity to temperature which patients are keen for researchers and clinicians to further explore in relation to PNH.

Anchor for Complications

COMPLICATIONS

Paroxysmal nocturnal haemoglobinuria (PNH) can lead to serious complications, largely due to the ongoing destruction of red blood cells. These can affect various parts of the body, impacting quality of life and potentially causing life-threatening issues. While some patients may experience few complications, others may face significant health risks that require careful management and regular monitoring. The most dangerous complications include blood clots, kidney damage and organ failure, amongst others.

It is also important to note that patients with few or no symptoms can still suffer from complications. The complications experienced by a PNH patient can change over time.

Early management of these complications with proper treatment and monitoring is essential to improving outcomes and quality of life for people with PNH.

Common Complications of PNH:

  • Blood clots (thrombosis): PNH increases the risk of developing blood clots in unusual places, such as the veins in the liver, around the brain or abdomen. These clots can lead to severe health problems, including strokes, heart attacks or pulmonary embolism (blockages in the lungs). Thrombosis is the leading cause the most common cause of death in PNH.
  • Kidney damage: This can vary from those mildly affected to kidney failure requiring dialysis treatment (this severity is very rare). Most patients with PNH do not develop significant kidney problems, but this needs to be carefully monitored. Occasionally, during an episode of severe haemolysis and haemoglobinuria this can cause a sudden (acute), but usually temporary, kidney failure. It is important that patients drink plenty of fluid to keep the kidneys well hydrated and to reduce the risk of acute kidney problems.
  • Pulmonary hypertension (PHT): This is high blood pressure in the arteries of the lungs, which can develop due to blood clots or the reduced oxygen-carrying capacity of the blood. It leads to breathlessness and heart strain.
  • Chronic anaemia: As PNH causes the destruction of red blood cells, the body may struggle to maintain normal blood levels, leading to chronic anaemia. This can cause persistent fatigue, weakness and reduced quality of life.
  • Gallstones: These are hardened deposits of digestive fluid that can form in the gall bladder, an organ that processes bile within the gut. If gallstones cause a blockage in the bile duct, they may result in sudden, worsening pain in the abdomen, nausea, back pain between the shoulder blades or pain in the right shoulder. PNH patients may develop gall bladder sludge, which can lead to similar symptoms to gallstones
  • Organ damage: Prolonged periods of haemolysis and the resulting lack of oxygen in the bloodstream can lead to damage in vital organs like the liver, heart and lungs.

Anchor for treatments

TREATMENTS AND CARE

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition, but advancements in PNH-specific treatments have greatly improved the outlook for patients. While there is no cure, a variety of treatment options can help manage symptoms, reduce complications, and improve quality of life.

The main goals of PNH treatment are to reduce the destruction of red blood cells, lower the risk of blood clots and manage other associated issues like anaemia.

Common Treatment Options for PNH

  • PNH specialised medicines: There are specialised medications including Fabhalta® (Iptacopan), PiaSky™ (Crovalimab-akkz), Soliris® (Eculizumab), Ultomiris® (Ravulizumab), Voydeya™ (Danicopan), that block different parts of the immune system (the complement system), which is responsible for destroying red blood cells in PNH patients. By preventing the breakdown of red blood cells, these drugs reduce PNH symptoms and the risk of blood clots. They are delivered in different ways including through infusions, tablets or subcutaneous injections depending on the treatment.
  • Anticoagulants (Blood thinners): With PNH increasing the risk of dangerous blood clots, patients may be prescribed blood thinners. These medications help prevent clots from forming.
  • Blood transfusions: Patients with severe anaemia usually need red blood transfusions to replace lost red blood cells which have been broken down by the haemolysis process. Transfusions can help improve energy levels and address the fatigue caused by low red blood cell counts for certain periods of time which vary between patients.
  • Iron and folic acid supplements: Since PNH often leads to iron loss through haemolysis, iron and folic acid supplements can help maintain healthy iron levels and support red blood cell production.

 

  • Allogeneic bone marrow transplantation (BMT): An allogeneic BMT is a process of replacing a person’s own bone marrow cells (which produce PNH blood cells) with healthy bone marrow cells from a donor. Bone marrow transplant is the only curative treatment for PNH, but has many significant complications which may occur in some patients. It is not very common for this to be recommended for patients with PNH where PNH specific treatments are available unless there is severe bone marrow failure co-existing with PNH e.g. aplastic anaemia. However BMT is used more often in countries where no PNH specific treatment is available.
  • Regular monitoring and supportive care: Ongoing care is essential for managing PNH. This includes regular blood tests to check for haemolysis, kidney function and the size of the PNH cell population (known as the PNH clone), as well as managing PNH symptoms.

These treatment options coupled with regular care help patients manage the condition, reduce the risks of complications and ideally lead a healthier life.

In most countries around the world PNH patients have no PNH-specific treatments due to very high prices. Biosimilars for C5 inhibition exist, but they have not significantly increased global patient access to PNH-specific treatments.