PNH Causes

Last updated March 13, 2023, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease that is not heritable but is caused, in most cases, by mutations in the PIGA gene in specific stem cells. The disorder is characterized by the destruction of blood cells, particularly the red blood cells that are responsible for transporting oxygen through the bloodstream. Red blood cell destruction may lead to symptoms like fatigue and the appearance of blood in the urine.

What causes PNH?

Hematopoietic stem cells, or HSCs, are cells that are present in the body’s bone marrow. They are responsible for giving rise to new blood cells — including red blood cells that carry oxygen through the bloodstream, white blood cells that fight off infections, and platelets that are small cell fragments involved in blood clotting.

Blood cells are relatively short-lived compared with other cells in the body. In fact, on average, a single red blood cell will only survive a few months in circulation. Therefore, HSCs replicate in order to produce new blood cells while replenishing the pool of HSCs within the bone marrow.

When HSCs divide, they make copies of their DNA, with one copy going into each of the newly formed cells. While this process is usually very efficient, sometimes mistakes can occur, resulting in new mutations being introduced into newly created HSCs. Progenitor cells carrying these mutations will continue to give rise to new HSCs and blood cells that also will carry the same mutations. Over time, this process results in HSC dysfunction and impairments in the blood cells they produce.

In most cases, PNH is caused by a mutation in the PIGA gene in HSCs. A more rare and inflammatory form of PNH, caused by mutations in another related gene called PIGT, also has been reported. Because HSCs reside within the bone marrow, PNH is also considered a type of bone marrow failure disorder.

Importantly, the mutation that causes PNH is acquired, meaning it randomly arises in HSCs during a person’s lifetime, due to sporadic errors in cell division, rather than being inherited. Someone with PNH cannot pass the disease-causing mutation on to any biological children. This is because only HSCs and blood cells are affected, not the sperm and egg cells involved in reproduction.

How does PNH affect red blood cells?

The PIGA gene that’s mutated in PNH is normally required for the production of a molecule called glycosylphosphatidylinositol (GPI). This molecule works as an anchor, helping to attach certain proteins to the surface of cells. As such, it’s known as GPI anchor.

Cells with PIGA mutations are unable to make GPI anchor, and as a result, end up with abnormally low levels of two GPI-anchored proteins on their surface. One of these is known as CD59, also called membrane inhibitor of reactive lysis or MIRL, while the other is called CD55 — also known as decay accelerating factor or DAF.

Given this, a diagnosis of PNH is generally made through analyses of blood cells to detect low or absent CD59, CD55, and GPI.

The CD59 and CD55 proteins normally act like a molecular identification badge for blood cells, signaling to the immune system that these cells are a healthy part of the body. Without these proteins, however, the immune system can mistake blood cells for an infectious agent, and launch an attack against them. The complement system, which is a group of immune proteins that are part of a person’s immune system, plays a central role in this attack in PNH. Many PNH treatments work by blocking complement activation.

The activation of the complement system and the resulting inflammatory attack destroy red blood cells. This leads to anemia, where the body lacks red blood cells to effectively transport oxygen to all its tissues and organs. Among the resulting symptoms are fatigue and shortness of breath.

Destroyed red blood cells release the oxygen-carrying protein hemoglobin into the bloodstream, causing excess amounts of this reddish protein to get into urine, a condition known as hemoglobinuria — one of the hallmarks of PNH.

Apart from red blood cells, the disease also can cause problems with white blood cells, making people with the disorder more prone to develop infections. Platelets also are affected, and their impairment is thought to play a role in clotting problems common in PNH patients.

PNH risk factors

PNH can develop at any age, but it most commonly starts between ages 30 and 40. It is believed that women are slightly more likely than men to develop PNH, although some studies have suggested there is no meaningful difference in disease risk based on sex or gender.

The risk of PNH is similar across people of all racial/ethnic groups and does not vary based on where a person lives.

People with aplastic anemia, another bone marrow condition where HSCs are not producing enough blood cells, are at an increased risk of developing PNH. It’s estimated that 15% to 25% of individuals with aplastic anemia also will develop this blood disorder. Conversely, PNH also is a risk factor for aplastic anemia, with up to 40% of PNH patients developing that bone marrow condition at some point.

Other bone marrow problems such as myelodysplastic syndromes (MDS) — a type of cancer caused by abnormal blood-forming cells in the bone marrow — also commonly co-occur with PNH. About 2% to 6% of PNH patients will go on to develop MDS over their lifetime.

PNH News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.