Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired blood disorder that affects the red blood cells, white blood cells, and platelets. This condition is characterized by the destruction of red blood cells (hemolysis), bone marrow dysfunction, and an increased risk of blood clots. While the disease may seem mysterious, medical research has uncovered clear insights into what causes PNH and how it develops.
The Root Cause: A Genetic Mutation
PNH is caused by a mutation in the PIGA gene (phosphatidylinositol glycan class A), which occurs in the hematopoietic stem cells of the bone marrow—the cells responsible for producing all blood cell types. This mutation is acquired, meaning it is not inherited from parents but develops during a person’s lifetime.
The PIGA gene plays a critical role in the creation of GPI anchors—molecules that attach certain protective proteins to the surface of blood cells. These protective proteins are essential for defending red blood cells against destruction by the body’s immune system, particularly the complement system, a part of the immune defense that helps remove harmful cells or pathogens.
In individuals with PNH, the mutation in the PIGA gene leads to the absence or deficiency of these GPI-anchored proteins—especially CD55 and CD59—on the surface of red blood cells. Without these proteins, red blood cells become vulnerable to attack by the complement system, resulting in chronic hemolysis, or the breakdown of red blood cells.
How the Disease Progresses
Once the PIGA mutation occurs in a stem cell, that defective cell begins to produce abnormal blood cells lacking the necessary protective proteins. Over time, these abnormal cells can outnumber healthy cells in the bone marrow, leading to a variety of symptoms and complications, including:
- Hemolytic anemia: Due to the ongoing destruction of red blood cells, patients often experience fatigue, weakness, and shortness of breath.
- Hemoglobinuria: A hallmark of the disease, hemoglobin from destroyed red cells is excreted in the urine, giving it a dark or reddish color—often more noticeable in the morning (hence the name “nocturnal”).
- Thrombosis: PNH increases the risk of dangerous blood clots, particularly in unusual locations such as abdominal veins or cerebral veins.
- Bone marrow failure: In some patients, the bone marrow’s ability to produce healthy blood cells is impaired, leading to low levels of red and white blood cells and platelets.
The Role of the Immune System
PNH is often linked to a broader group of bone marrow disorders called aplastic anemia and myelodysplastic syndromes. In these cases, the immune system may mistakenly attack and damage the bone marrow, creating an environment where PNH-mutated cells have a survival advantage over normal cells. This immune-mediated damage may help explain why the PNH clone expands and becomes dominant in some individuals.
Who Is at Risk?
Since the PIGA gene mutation is acquired rather than inherited, anyone can develop PNH. However, it is more commonly diagnosed in young adults and slightly more prevalent in females. The disease is rare, affecting an estimated 1 to 1.5 people per million annually.
Diagnosis and Treatment
PNH is typically diagnosed using flow cytometry, a test that measures the presence (or absence) of GPI-anchored proteins on the surface of blood cells. Additional tests may include blood counts, LDH levels (a marker of cell breakdown), and urine tests for hemoglobin.
Treatment depends on the severity of the condition. For many, complement inhibitors such as eculizumab or ravulizumab have dramatically improved outcomes by blocking the immune attack on red blood cells. Other options may include blood transfusions, bone marrow stimulants, or in severe cases, bone marrow transplantation.
Uncovering the Cause to Empower Better Care
Paroxysmal Nocturnal Hemoglobinuria is caused by a single genetic mutation with widespread effects on the blood and immune system. Understanding its origins and how the disease progresses is key to managing symptoms and improving quality of life. With advancing research and effective treatments, people with PNH have more hope than ever for a stable and fulfilling life.