Paroxysmal nocturnal hemoglobinuria (PNH) may be rare, but its impact on the body can be profound. It’s a disease that often leads to anemia (low levels of red blood cells) or other symptoms, such as sudden fatigue or dark urine. Out of every 1 million people in the U.S., it’s estimated that about 12 or 13 live with PNH.

In this article, we’ll explore key paroxysmal nocturnal hemoglobinuria characteristics, the causes of this condition, and the latest treatments that can help you manage it to improve your quality of life.

What Is PNH?

PNH is a type of hemolytic anemia, a condition in which red blood cells (also known as erythrocytes) are destroyed faster than they can be replaced. This process, known as hemolysis, occurs when the immune system — specifically the complement system — mistakenly attacks and breaks apart these red blood cells.

The complement system helps keep your body healthy by finding and destroying disease-causing invaders like viruses and bacteria. Normal red blood cells are coated with proteins that signal to your complement system that the cells are safe and shouldn’t be attacked. However, in PNH, genetic mutations result in red blood cells without these signaling proteins. The complement system assumes these red blood cells are dangerous invaders and destroys them.

PNH is also caused by problems with your hematopoietic stem cells (HSCs). These cells are found in your bone marrow and are responsible for making all of the different cells in your blood. When these abnormal stem cells produce defective red blood cells, it contributes to both anemia and an increased risk of blood clotting, also known as thrombosis. Abnormal HSCs may lead to low levels not only of red blood cells, but also of white blood cells (which help fight infection) and platelets involved in the blood-clotting system.

Symptoms and Key Characteristics of PNH

Common PNH signs and symptoms include:

• Hemoglobinuria (darkened or reddish urine, often noticed first thing in the morning)
• Headaches
• Muscle or joint pain
• Abdominal pain
• Anemia (low levels of red blood cells), leading to fatigue, shortness of breath, irregular heartbeats, pale skin, jaundice (yellowed skin), or irritability
• Abnormal bruising or bleeding
• Frequent infections
• Swallowing problems
• Erectile dysfunction (trouble achieving or maintaining an erection)

Types of PNH

Your doctor may classify your PNH into a category based on your symptoms. In classic PNH, people develop some of the common symptoms listed above. Subclinical PNH occurs when a small number of abnormal PNH cells can be detected, but you don’t have symptoms. In severe cases of PNH, there may be a high risk of dangerous blood clots, especially in certain locations like the abdomen (belly). If your symptoms are severe, you may have PNH along with a bone marrow failure syndrome, meaning that HSCs produce very few blood cells.

What Causes PNH?

Two factors lead to PNH. Your HSCs develop a gene mutation, and then these defective cells start growing out of control.

PNH is typically caused by a mutation (change) in the PIGA gene. This gene helps make a protein called‌ phosphatidylinositol glycan. It acts as an anchor protein on the surface of red blood cells to signal to the immune system they belong there and shouldn’t be attacked. Without a working PIGA gene, your red blood cells are left unprotected and get destroyed by your complement system. This gene mutation developed at some point during your life. It wasn’t inherited from your parents, and you won’t pass it on to your children.

If just a few HSCs have a gene mutation, you may never experience symptoms. Many people have a small number of PNH cells and never find out. However, PNH develops when the abnormal HSCs expand too quickly and crowd out your normal HSCs.

Your HSCs may grow out of control if they develop additional gene changes besides the PIGA mutation. If your immune system is suppressed, this might also prevent it from getting rid of these damaged cells. This can happen if you develop bone marrow failure due to a condition like aplastic anemia.

Conditions Related to PNH

If you have PNH, you may have to watch out for other conditions related to paroxysmal nocturnal hemoglobinuria that can occur alongside this blood disorder.

PNH often occurs with conditions that cause bone marrow failure, including aplastic anemia and myelodysplastic syndromes (MDS). These conditions are also caused by problems with the HSCs, leading to low levels of one or more blood cell types. Aplastic anemia and MDS may occur first and lead to an increased risk of PNH, or they may develop after you have a PNH diagnosis.

PNH can also lead to other conditions, including:

• Pulmonary hypertension (high blood pressure in the blood vessels that lead from your heart to your lungs)
• Life-threatening thrombosis
• Paroxysmal cold hemoglobinuria (another disorder in which immune cells mistakenly attack red blood cells)
• Acute myeloid leukemia
• Meningitis, inflammatory bowel disease, or other types of inflammation-related problems
• In rare cases, various types of kidney damage or kidney disease

Schedule regular follow-up visits with your health care team to make sure your treatments are working, and to confirm that you aren’t at risk of developing further health problems.

How Is PNH Diagnosed?

Some people first realize they have PNH after they develop symptoms. Others may discover a problem when routine blood tests come back with abnormal results.

Blood tests that can uncover signs of PNH include:

• Complete blood count (CBC) — If you have PNH, this test may show that you have low levels of red blood cells, white blood cells, platelets, or hemoglobin (a protein normally found in red cells).
• Reticulocyte count — Reticulocytes are immature red blood cells. Levels may rise during PNH as your body tries to replace the destroyed red blood cells.
• Haptoglobin test — You may have PNH if you have low levels of haptoglobin, a protein that helps get rid of any extra hemoglobin that spills into your bloodstream when red blood cells are destroyed.
• Bilirubin test — PNH is often characterized by high levels of bilirubin, a pigment made when red blood cells break down.
• Lactate dehydrogenase (LDH) test — LDH is an enzyme that serves as a sign of cell damage. Levels may rise if you’re experiencing hemolysis.

While these diagnostic tests show certain PNH-related problems, other health conditions may also lead to the same test results. Doctors usually confirm PNH with a test called flow cytometry, which detects proteins attached to the outer membranes of blood cells. If you have PNH, flow cytometry will show that your cells lack the proteins that offer protection from the complement system.

For more detailed PNH information, your health care team may also recommend a bone marrow test to look for signs of bone marrow failure and determine whether your HSCs can produce enough healthy blood cells. During this test, your doctor will remove a small sample of cells by inserting a long needle into the bone marrow in your pelvic bone or breastbone. These cells will then be analyzed to look for abnormalities.

Treatments for PNH

Your doctor will recommend PNH treatments based on your symptoms and whether you have bone marrow failure. If you have very mild PNH, you may not need treatment right away. Your doctor may monitor your condition and begin treatment if your PNH worsens.

Certain medications can block your complement system, preventing immune cells from attacking your red blood cells. Complement inhibitors include:

• Crovalimab (PiaSky)
• Danicopan (Voydeya)
• Eculizumab (Bkemv, Soliris)
• Iptacopan (Fabhalta)
• Pegcetacoplan (Empaveli)
• Ravulizumab (Ultomiris)

If you experience bone marrow failure due to aplastic anemia or another condition, your doctor may recommend taking immunosuppressive therapy to prevent your immune system from killing your HSCs.

While living with PNH, you may also receive supportive care. These treatments can help improve symptoms and boost your quality of life. Supportive care includes:

• Dietary supplements including iron or folate, since your body needs these nutrients to make more blood cells
• Growth factors such as erythropoietin, which encourage your HSCs to make more red blood cells
• Hormones called androgens that spur the production of red blood cells
• Blood transfusions, in which blood cells from a donor are given as an infusion into your veins
• Anticoagulants (blood thinners), medications that help prevent blood clots

The only treatment that can potentially cure PNH is bone marrow transplantation. During this procedure, you are given chemotherapy to kill your abnormal HSCs, and then you receive an infusion of healthy HSCs from a donor. A bone marrow transplant may enable your body to start producing normal blood cells again. However, this treatment is usually only recommended for those with life-threatening PNH, as it’s dangerous and doesn’t always work.

Researchers are continually creating new treatments and testing them through clinical trials. If you are interested in participating in the latest research, ask your doctor for information about current and upcoming studies.

Your Prognosis With PNH

The prognosis (outlook) for PNH has improved greatly in recent decades. In the past, people with PNH lived for an average of 10 to 22 years after the condition developed. However, complement inhibitors now help people live longer. Some experts predict that people with PNH now live as long as those without the condition, although additional studies are needed.

Various factors may also affect your individual prognosis. For example, you may have a poor prognosis if you also have aplastic anemia or MDS. If you’re diagnosed with PNH, ask your hematology specialist (doctor who treats blood disorders) about what to expect based on your own health considerations.

Find Your Team

On myPNHteam, the site for people with paroxysmal nocturnal hemoglobinuria and their loved ones, members come together to ask questions, offer advice, and share their stories with others who understand life with PNH.

Have you been diagnosed with PNH? Do you have any advice for managing life with PNH? Share your experience in the comments below, or start a conversation on your Activities page.