Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease that leads to low levels of red blood cells. If you have PNH, your healthy red blood cells are destroyed when they shouldn’t be, and your body can’t make enough to replace the ones that were lost.

Two key factors are involved in the development of PNH:

• A gene mutation (variation) occurs in a bone marrow stem cell, creating abnormal blood cells without the protective shield they need.
• These abnormal cells grow and spread, especially if the bone marrow is already weak, making them easy targets for the immune system.

Although PNH arises from genetic changes, it is not inherited and typically does not run in families. PNH is also not associated with specific lifestyle or environmental risk factors that increase the likelihood of developing the condition.

Here are the top facts to know about what causes PNH.

How Do Your Blood Cells Normally Develop?

To better understand PNH, it helps to learn how your body typically makes new blood cells. Blood cell production happens in the bone marrow, the soft tissue inside certain bones. Within the bone marrow, a special type of cell called hematopoietic stem cells (HSCs) makes all of the blood cells within your body. These include:

• Erythrocytes (red blood cells) — Cells that carry oxygen throughout your body
• Leukocytes (white blood cells) — Immune cells that fight infection
• Platelets — Cell fragments that help your blood clot after an injury

PNH isn’t believed to be triggered by environmental factors like diet, physical activity levels, or exposure to chemicals.

Red blood cells use a protein called hemoglobin to help carry oxygen from your lungs to the tissues throughout your body.

The Complement System

Your immune system, including certain types of white blood cells, uses multiple mechanisms to fight disease and protect your health. One of these mechanisms, the complement system, changes when you develop PNH.

Normally, your complement system:

• Recognizes and attacks germs or other foreign substances
• Heals injuries
• Gets rid of old or damaged cells

How does your complement system “know” whether a cell is healthy or potentially harmful? Cells throughout your body, including your blood cells, have a group of proteins on their outer surface. These proteins act as a shield, preventing your complement system from becoming activated and attacking your healthy cells. This helps prevent hemolysis (the breakdown of red blood cells).

1. PNH Starts With a Change in a Gene

The first step of PNH occurs when a gene change causes your complement system to attack your red blood cells. This condition is almost always caused by a mutation in a gene called PIGA. The PIGA gene is responsible for helping your body make the protein shield that protects your cells from the complement system. When a cell doesn’t have a working PIGA gene due to a mutation, it’s vulnerable to attack from your complement system.

PNH is almost always caused by a mutation in a gene called PIGA.

In PNH, a small group of HSCs in your bone marrow have a PIGA mutation. These HSCs make red blood cells that also have the same mutation. The abnormal red cells, also called PNH cells, have no defense against the complement system and are destroyed.

2. PNH Isn’t Usually Hereditary

Children don’t usually inherit PNH — it can’t be passed down from parent to child.

PNH is caused by a somatic mutation, which occurs in just a couple of cells in the body. These mutations develop throughout a person’s life and aren’t transferred to future generations. Somatic mutations are sometimes caused by environmental factors, such as high doses of radiation, but no environmental factors have been linked to PNH. Health experts believe the somatic mutations that cause PNH occur randomly.

Inflammatory PNH

In very rare cases, PNH can be caused by a mutation in a different gene called PIGT. This leads to a form of PNH with inflammatory symptoms such as a rash, inflammatory bowel disease, or meningitis (swelling of the membrane that covers your brain and spinal cord).

Cells have two copies of every gene, including the PIGT gene. Inflammatory PNH is caused by two gene mutations — one in each PIGT copy. One mutation is inherited from a parent, while the other is a somatic mutation that develops later on. Therefore, this rare type of PNH may run in families, although an additional mutation is still needed for PNH to develop. This means that even if one of your parents had PNH, you may not ever develop it.

3. Cells With the Gene Change Grow and Take Over

A PIGA mutation alone is not enough to cause PNH. In fact, many people have a small number of HSCs with a mutated PIGA gene and never develop PNH. Usually, these cells are eliminated or kept under control by the complement system.

The second step of PNH development occurs when the cells with PIGA or PIGT gene mutations take over. The mutated HSCs, known as PNH clones, grow more numerous and produce increasing numbers of abnormal red blood cells that end up destroyed by the complement system.

Scientists don’t entirely understand why the mutated cells reproduce and cause PNH in some people but not in others. However, they have identified a few possibilities.

Bone Marrow Failure

PNH frequently occurs along with bone marrow failure — a condition that happens when stem cells in the bone marrow aren’t producing enough blood cells. In people with PNH, this issue is often caused by a bone marrow disorder such as aplastic anemia or myelodysplastic syndrome. These conditions can encourage healthy HSCs to be destroyed while abnormal HSCs grow.

Other Causes of PNH Cell Growth

HSCs with PIGA mutations may also grow out of control because they develop additional gene mutations that help them expand and form new cells more quickly. Additionally, other problems with the immune system may lead to PNH. Normally, the complement system can destroy HSCs with mutations, but if the immune system becomes weakened, the cells with abnormalities may grow out of control and take over.

About 1 out of 10 people with aplastic anemia will eventually be diagnosed with PNH.

4. Having Aplastic Anemia Is a Risk Factor for PNH

The only risk factor for PNH researchers have identified so far is having aplastic anemia. About 1 out of 10 people with this form of life-threatening anemia will be diagnosed with PNH.

PNH can affect people of all ages, races, and ethnicities. However, there are no widely recognized characteristics, aside from a history of aplastic anemia, that significantly increase the risk of developing PNH. According to the National Organization for Rare Disorders (NORD), PNH may develop more often in people from Southeast Asia and the Far East, for whom aplastic anemia tends to be more common.

5. There’s No Way To Prevent PNH

PNH is caused by random gene mutations, making it impossible to prevent. These mutations occur spontaneously and are not inherited from your parents. PNH is also not linked to environmental factors like diet, exercise, or chemical exposure.

That said, PNH is more likely to develop in people with aplastic anemia. If you have this condition, it’s crucial to work closely with your health care team to manage it effectively. Proper treatment and monitoring can help reduce complications and support your overall health.

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 tips for others living with this condition? Share your experience in the comments below, or start a conversation on your Activities page.