Paroxysmal Nocturnal Haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare blood disorder where the body’s immune system mistakenly attacks and destroys its own red blood cells, leading to serious complications including anaemia, blood clots, and kidney problems.

Table of contents

• What is Paroxysmal Nocturnal Haemoglobinuria?
• Who is Affected by PNH?
• What Causes PNH?
• Signs and Symptoms
• How is PNH Diagnosed?
• Treatment Options
• Living with PNH
• Outlook and Life Expectancy

What is Paroxysmal Nocturnal Haemoglobinuria?

Paroxysmal nocturnal haemoglobinuria, commonly known as PNH, is a rare blood disease where red blood cells break apart too early^[1]. The name describes one of its most distinctive symptoms: passing dark-colored urine, especially in the morning. “Paroxysmal” means sudden and irregular, “nocturnal” means at night, and “haemoglobinuria” means the presence of haemoglobin (the red protein that carries oxygen in your blood) in your urine^[6].

However, not everyone with PNH experiences dark urine. The condition causes a broader range of problems throughout the body^[1]. PNH is considered an acquired disease, which means it develops during a person’s lifetime rather than being inherited from parents^[3].

The disease affects three main types of blood cells: red blood cells that carry oxygen, white blood cells that fight infection, and platelets that help blood clot^[3]. When these cells are destroyed, it leads to many of the symptoms and complications seen in PNH.

Who is Affected by PNH?

PNH is extremely rare. Only about 6 per 1 million people are diagnosed with PNH each year^[1]. Globally, it is estimated that around 20,000 people have PNH^[5].

The condition most commonly affects people between the ages of 30 and 40 years old, although it can occur at any age^[1][2]. Women are slightly more likely than men to develop the disease^[1].

Many people with PNH also have other bone marrow disorders. Often, individuals who have aplastic anaemia or myelodysplastic syndrome develop paroxysmal nocturnal haemoglobinuria^[1][3].

What Causes PNH?

PNH occurs because of a genetic change that happens during a person’s lifetime. This change affects a gene called PIGA, which is responsible for creating protective proteins on the surface of blood cells^[1][3].

The problem begins in the bone marrow, the spongy tissue inside certain bones where blood cells are made. In PNH, the PIGA gene in one stem cell (the early cell that develops into blood cells) mutates or changes^[1]. This abnormal stem cell then divides and makes more abnormal stem cells, which eventually become abnormal red blood cells and platelets.

These abnormal blood cells are missing important protective proteins called CD55 and CD59^[2][5]. These proteins normally shield blood cells from attack by the complement system, which is part of the body’s immune system that helps fight infection.

Without this protective shield, the complement system mistakenly attacks the body’s own red blood cells, causing them to fall apart. This process is called haemolysis^[1]. When red blood cells break down, they release haemoglobin into the bloodstream. The body tries to clear this excess haemoglobin, but it cannot keep up with the amount being released in PNH^[1].

The destruction of red blood cells also depletes the body’s supply of nitric oxide, an important substance that helps blood vessels work properly. Without enough nitric oxide, people with PNH may experience painful muscle spasms in the stomach, throat, and back^[1].

Signs and Symptoms

PNH causes a wide variety of symptoms that can differ greatly from one person to another^[5]. Not everyone experiences every symptom, and symptoms may appear gradually, making the disease difficult to recognize^[4][5].

The most common symptoms include^[1][3]:

• Extreme tiredness and weakness
• Shortness of breath
• Rapid heartbeat
• Abnormally pale skin
• Dark-colored urine, especially noticeable in the morning
• Headaches
• Abdominal pain
• Back pain
• Difficulty swallowing or pain during swallowing
• Erectile dysfunction in men

Many of these symptoms result from anaemia, which is a shortage of red blood cells in the blood^[3]. The painful symptoms, such as abdominal pain and difficulty swallowing, typically occur when red blood cell breakdown is rapid and are related to muscle spasms^[4].

People with PNH may also experience bruising and bleeding problems, even having difficulty controlling minor bleeding^[1]. Small red dots may appear on the skin, indicating bleeding below the skin’s surface. Some people are more prone to infections due to a shortage of white blood cells^[3].

One of the most serious complications of PNH is the formation of blood clots, known as thrombosis. About 40% of people with PNH develop thrombosis at some point in their illness^[4]. Blood clots can form in common sites like the legs or in more unusual locations such as the veins of the liver or abdomen^[4]. Thrombosis is the main cause of severe complications and death in PNH^[4][7].

How is PNH Diagnosed?

Diagnosing PNH can be challenging because it is so rare and its symptoms are common to many other diseases. Fewer than 40% of people with PNH receive a diagnosis within 12 months of when symptoms first appear, and for 24% of people, diagnosis can take five years or longer^[5].

Healthcare providers look for signs of intravascular haemolysis (the destruction of red blood cells within blood vessels), thrombosis, and cytopenia (reduced number of blood cells) as clinical indications of PNH^[5].

The primary test used to diagnose PNH is called flow cytometry, which examines blood cells to see if they are missing the protective proteins CD55 and CD59^[2]. This test can detect even small populations of abnormal cells.

Other tests may include blood counts to check for anaemia, tests to measure haemoglobin in the urine, and tests to assess kidney and liver function. Healthcare providers may also perform tests to rule out other conditions with similar symptoms.

Treatment Options

While PNH cannot be completely cured with medication alone, several treatment options are available to control symptoms and prevent complications^[1].

Complement Inhibitor Medications

The main treatment for PNH involves medicines that block the complement system and prevent it from destroying red blood cells^[8]. These medications have dramatically changed the outlook for people with PNH.

Several complement inhibitor medications are now available^[10][14]:

• Eculizumab (Soliris) – Given by intravenous infusion once every two weeks. It was the first drug approved specifically for PNH and has been used since 2007^[14].
• Ravulizumab (Ultomiris) – Given by intravenous infusion once every eight weeks, approved in 2018 and 2019^[14].
• Pegcetacoplan (Empaveli) – Given by infusion twice weekly, this targets a different part of the complement system^[12].
• Iptacopan – An oral medication taken by mouth, approved in 2023^[10].
• Danicopan – Approved in 2024 as an add-on therapy for patients who still experience symptoms while on other complement inhibitors^[10].

These medications do not cure PNH, but they control symptoms and reduce the risk of serious complications like blood clots. People typically need to take these medicines for the rest of their lives or until the disease goes into remission^[12].

Because complement inhibitors block part of the immune system, they increase the risk of certain infections, particularly meningitis. Before starting treatment, people must receive vaccines against meningococcal bacteria and may need to take preventive antibiotics^[14].

Unfortunately, due to the very high cost of these treatments (approximately £300,000 per person per year), they are not available to all PNH patients globally^[14].

Stem Cell Transplantation

The only treatment that can cure PNH is an allogeneic stem cell transplant, also called a bone marrow transplant^[8][12]. This procedure replaces the abnormal stem cells in the bone marrow with healthy ones from a donor, usually a close relative.

However, stem cell transplantation carries significant risks, including serious infection and organ damage. Because of these risks, it is only recommended for people with very severe PNH who have life-threatening complications or severe bone marrow failure^[7][12].

Supportive Care

Additional treatments help manage specific symptoms and complications^[10][12]:

• Blood transfusions to treat severe anaemia
• Iron and folic acid supplements to support red blood cell production
• Blood thinners to prevent or treat blood clots
• Medications to suppress the immune system in certain cases

Living with PNH

People with PNH can take several steps to manage their condition and maintain a good quality of life.

Daily Self-Care

Maintaining regular routines and healthy habits is important. This includes getting adequate sleep, staying hydrated by drinking plenty of water, and eating a balanced diet rich in fruits, vegetables, and whole grains while limiting processed foods and excess salt^[15][20].

Regular but gentle exercise can help, though people should talk with their doctor about which activities are appropriate. Heavy exercise may cause problems in some cases^[15].

Infection Prevention

Staying current with vaccinations is crucial for people with PNH, especially those taking complement inhibitor medications. People should also talk with family members and caregivers about keeping their vaccinations up to date^[15].

Medical Precautions

Before any surgery or medical procedure, people with PNH should talk with their specialist, as surgery carries specific risks including increased chances of blood clots or serious bleeding^[15].

Travel requires advance planning. Flying in airplanes or being at high elevations can cause issues for people with anaemia because there is less oxygen in these situations. People should talk with their doctor and have blood counts checked before traveling^[15].

Pregnancy Considerations

Pregnancy in women with PNH requires careful management. Having a baby increases the risk of blood clots, bone marrow problems, and very high blood pressure. There are also some risks for babies, such as low birth weight or slow development^[15].

Women who are pregnant or thinking about becoming pregnant should work with an obstetrician familiar with PNH and high-risk births. The complement inhibitor eculizumab can be safely used during pregnancy^[14].

Emotional Support

Living with a chronic condition like PNH can be stressful. Building a support network of friends, family, and other people with PNH can make a significant difference. Some people benefit from counseling or other complementary therapies such as meditation or massage^[15][20].

Keeping a record of symptoms, medications, and lifestyle changes can help people stay organized and communicate effectively with their healthcare team^[15].

Outlook and Life Expectancy

The outlook for people with PNH has improved dramatically over the past 15 years. Several decades ago, only 50% of people with PNH survived for 10 years after diagnosis. Today, with modern treatments like complement inhibitors, survival has improved to more than 75%^[2].

Treatment with complement inhibitors has transformed PNH from a life-threatening condition to a manageable chronic disease. These medications reduce symptoms and complications to such an extent that life expectancy may now be similar to that of the general population^[4][14].

The main cause of death in PNH remains thrombosis, which is why preventing and treating blood clots is so important^[7]. People with PNH also have an increased risk of developing leukemia, a cancer of blood-forming cells^[3].

In a small number of cases, the signs and symptoms of PNH may disappear on their own^[3]. However, most people require ongoing treatment and monitoring.