Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease that leads to low levels of red blood cells. If you have this condition, 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.

For someone to have PNH, two main steps need to occur:

• You develop a particular gene mutation (variation) that leads to abnormal blood cells.
• The abnormal blood cells grow quickly and crowd out your healthy blood cells.

Although PNH is caused by changes in your genes, it isn’t usually passed down through families. In general, PNH isn’t linked to any risk factors that can increase your chances of developing the condition.

How Do Your Blood Cells Normally Develop?

To better understand PNH, it helps to first learn about how your body typically makes new blood cells. Blood cell production happens in the bone marrow, the soft tissue found inside certain bones. Within the bone marrow, a special type of cells called hematopoietic stem cells (or HSCs) is responsible for making all of the blood cells within your body. These include red blood cells (also called erythrocytes), white blood cells (immune cells that fight infection), and platelets (cell fragments that help your blood clot after an injury).

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 several strategies to fight disease and keep you healthy. One of these strategies, the complement system, undergoes 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 potentially harmful or whether it is one of your own healthy cells? 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).

The Genetic Causes of PNH

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.

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.

Is PNH Hereditary?

PNH is usually not hereditary. In other words, 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. 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 characterized by 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 you may not ever have PNH even if one of your parents had the condition.

Expansion and Growth of PNH Cells

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 grow more numerous and produce increasing numbers of abnormal red blood cells that end up getting destroyed by the complement system.

Experts 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 (MDS). 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 mutant HSCs, but if the immune system becomes weakened, the cells with abnormalities may grow out of control and take over.

PNH Risk Factors

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 go on to be diagnosed with PNH.

There aren’t any other characteristics that seem to lead to an increased risk of PNH. It affects people of all ages, races, and ethnicities. PNH does more frequently develop in people of Asian descent, although this is likely because this group has a higher risk for developing aplastic anemia.

Can PNH Be Prevented?

There is no certain way to avoid PNH. This condition is caused by gene mutations that occur randomly, so you can’t stop them from happening. PNH doesn’t typically develop as a result of genes from your parents. It isn’t believed to be triggered by environmental factors like diet, physical activity levels, or exposure to chemicals.

Because PNH more often occurs in people with aplastic anemia, it’s important to get proper treatment if you’re living with this blood disorder. Work with your health care team to keep your aplastic anemia under control as well as you can.

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.