Imagine a condition where your own immune system, designed to protect you, systematically destroys your red blood cells. Imagine this destruction leading not only to profound fatigue but also to a life-threatening risk of blood clots in unusual parts of the body. This is the reality for individuals diagnosed with Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare, complex, and serious blood disease. It is caused by a tiny genetic mutation in a single stem cell that multiplies and eventually disrupts the body’s most fundamental processes. While a PNH diagnosis can be frightening, the last two decades have seen revolutionary advancements in treatment that have transformed the prognosis, allowing patients to manage their condition and live longer, healthier lives.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired blood disorder characterized by the premature destruction of red blood cells by a part of the complement system. Despite its name, which can be misleading, PNH is a chronic and constant condition. Let’s look at the name’s origins:

• Paroxysmal: Means occurring in sudden, recurring episodes.
• Nocturnal: Means happening at night.
• Hemoglobinuria: Means the presence of hemoglobin (the protein that carries oxygen in red blood cells) in the urine.

The name comes from the classic, historical description of some patients noticing dark, reddish-brown urine, particularly in their first morning urination. However, it is now understood that the underlying destruction of red blood cells (hemolysis) is a continuous process that occurs 24 hours a day, and only a minority of patients experience the classic symptom of nocturnal hemoglobinuria.

The core problem in PNH is that a population of a person’s blood cells is missing a protective protein shield on their surface. To understand this, it is helpful to use an analogy. Think of the complement system as the “navy” of your immune system, a fleet of powerful protein “submarines” that constantly patrol your bloodstream to identify and destroy any foreign or abnormal cells. Your normal, healthy blood cells are covered in a special “friendly force field” made of proteins that essentially tells these submarines, “Don’t shoot, I’m one of you.”

In PNH, due to a genetic mutation, a whole line of blood cells is produced without this protective force field. When these vulnerable cells circulate in the bloodstream, the complement submarines see them as unprotected targets and destroy them on sight. This constant, complement-mediated destruction of red blood cells is the central feature of the disease.

The direct cause of PNH is a somatic mutation in the PIGA gene of the stem cells in the bone marrow.

• Somatic mutation means that the genetic change is acquired during a person’s lifetime in a single cell; it is not inherited from parents and cannot be passed on to children.
• The PIGA gene, located on the X chromosome, holds the instructions for making a protein that is essential for creating a structure known as the glycosylphosphatidylinositol (GPI) anchor.

The GPI anchor acts like a “docking station” on the surface of a cell. Its job is to hold certain proteins in place, tethering them to the cell membrane. In blood cells, two of the most important proteins held by this anchor are CD55 and CD59. These two proteins are the key components of the “protective force field” that shields the cells from an attack by the complement system.

When the PIGA gene in a blood-forming stem cell is mutated, that stem cell and all its progeny lose the ability to make a functional GPI anchor. Without this docking station, the protective CD55 and CD59 proteins cannot attach to the cell surface, leaving the cell completely vulnerable to the complement system. This single faulty stem cell then multiplies, producing a large population (or “clone”) of unprotected red blood cells, white blood cells, and platelets.

The process of developing clinically significant PNH is thought to be a “two-hit” event. It requires more than just the initial mutation.

1. The PIGA Mutation: A spontaneous mutation occurs in the PIGA gene of a single hematopoietic (blood-forming) stem cell in the bone marrow. These mutations are thought to happen randomly and rarely in all people, but they usually have no consequence.
2. Clonal Expansion: For PNH to develop, this single mutated stem cell must undergo clonal expansion, meaning it must multiply and proliferate until it makes up a significant portion of the blood cells being produced.

This clonal expansion often happens in the setting of a damaged or failing bone marrow. PNH is very strongly associated with aplastic anemia, a condition where the bone marrow fails to produce enough blood cells. It is believed that in the hostile environment of a failing marrow, the PNH stem cells have a unique survival advantage that allows them to thrive and expand while the normal stem cells die off. This is why many patients with aplastic anemia are found to have a small PNH clone, and some will go on to develop clinical PNH.

PNH symptoms vary widely and may range from mild to life-threatening. They result from three main problems: hemolysis, bone marrow dysfunction, and blood clots.

1. Symptoms of Intravascular Hemolysis (Red Blood Cell Destruction): When red blood cells are destroyed within the blood vessels, they release large amounts of hemoglobin into the bloodstream. This free hemoglobin causes many classic PNH symptoms.

• Anemia: The loss of red blood cells leads to anemia, causing profound fatigue, weakness, pale skin, and shortness of breath.
• Hemoglobinuria: When the level of free hemoglobin in the blood overwhelms the body’s ability to process it, it is filtered by the kidneys and passes into the urine, turning it dark red or cola-colored.
• Jaundice: The breakdown of hemoglobin produces bilirubin, which can cause a yellowing of the skin and eyes.
• Other Symptoms from Nitric Oxide Depletion: Free hemoglobin in the blood scavenges and depletes a vital molecule called nitric oxide. Nitric oxide is crucial for relaxing smooth muscles. Its depletion can lead to:
  • Esophageal spasms and difficulty swallowing.
  • Abdominal pain.
  • Erectile dysfunction in men.
  • Pulmonary hypertension (high blood pressure in the lungs).

2. Thrombosis (Blood Clots): The constant destruction of platelets and other factors creates a “hypercoagulable state,” making patients extremely prone to forming blood clots. These clots can form in dangerous and unusual locations, such as:

• Liver veins (leading to Budd-Chiari syndrome).
• Abdominal and intestinal veins.
• Brain veins (cerebral venous thrombosis).
• The deep veins of the legs (DVT), which can travel to the lungs (pulmonary embolism).

3. Bone Marrow Dysfunction (Cytopenias): Because PNH often arises from a background of bone marrow failure, many patients also have low counts of other blood cells.

• Low White Blood Cells (Neutropenia): Can lead to an increased risk of serious infections.
• Low Platelets (Thrombocytopenia): Can cause easy bruising and bleeding.

Diagnosis

Diagnosis is made using specialized blood tests that detect PNH clones, populations of blood cells lacking protective proteins.

• Initial Blood Tests: A complete blood count (CBC) will show anemia and may show low white cells and platelets. Blood tests for LDH and bilirubin will be very high, indicating hemolysis.
• Flow Cytometry: It is the gold standard test for diagnosing PNH. It is a highly specialized blood test that can accurately identify PNH cells.
• Bone marrow biopsy: It is also often performed to assess the overall health of the bone marrow and to check for underlying aplastic anemia or another bone marrow failure syndrome.

Treatment

The treatment goals for PNH are to control the symptoms of hemolysis, reduce the life-threatening risk of thrombosis, and improve the patient’s quality of life. The development of targeted therapies has revolutionized disease management.

1. Complement Inhibitors: This class of drugs is the standard of care for patients with significant PNH symptoms.

• Mechanism: These are monoclonal antibodies that work by blocking a specific protein in the complement system called C5. By inhibiting C5, these drugs prevent the final step of the complement cascade that leads to destruction of PNH red blood cells. This effectively stops the intravascular hemolysis.
• Primary Medications:
  • Eculizumab: Given as an intravenous (IV) infusion every two weeks.
  • Ravulizumab: A newer, longer-acting version given by IV infusion every eight weeks.
• Benefits: These drugs are highly effective at controlling hemolysis, reducing the need for transfusions, alleviating symptoms like fatigue and abdominal pain, and, most importantly, dramatically reducing the risk of blood clots.
• Considerations: These targeted therapies are also among the most expensive medications in the world, and access can be a significant challenge for many patients depending on their healthcare system and location. They also increase the risk of infection with a specific type of bacteria (Neisseria meningitidis), so patients must be vaccinated against meningitis.

2. Supportive Care: This remains a crucial part of management, especially for patients with milder disease or for whom complement inhibitors are not available.

• Blood Transfusions: To manage severe anemia.
• Anticoagulation (Blood Thinners): To prevent or treat blood clots.
• Folic Acid and Iron Supplementation: To support the production of new red blood cells.

3. Bone Marrow (Stem Cell) Transplant: A bone marrow transplant is currently the only curative treatment for PNH. However, it is a very high-risk procedure with significant potential complications and is typically reserved for young people.

Paroxysmal Nocturnal Hemoglobinuria is a rare and formidable disease, born from a single genetic misstep in a stem cell that leads to a cascade of devastating consequences, chronic destruction of blood cells, debilitating fatigue, and a high risk of life-threatening blood clots. For decades, only supportive care was available. Today, the landscape has been transformed. The development of complement-inhibiting therapies has turned PNH into a manageable chronic condition for many, drastically reducing its most dangerous complications and restoring quality of life.

• Aplastic Anemia and MDS International Foundation (AAMDSIF). (2021). Paroxysmal nocturnal hemoglobinuria. Retrieved from https://www.aamds.org/diseases/paroxysmal-nocturnal-hemoglobinuria-pnh
• National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Paroxysmal nocturnal hemoglobinuria. Retrieved from https://rarediseases.info.nih.gov/diseases/7319/paroxysmal-nocturnal-hemoglobinuria
• National Organization for Rare Disorders (NORD). (2022). Paroxysmal nocturnal hemoglobinuria. Retrieved from https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria-pnh/