What Is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

PNH received its name long before scientists understood many aspects of the condition. “Paroxysmal” means occurring in episodes, “nocturnal” means at night, and “hemoglobinuria” refers to the presence of the protein hemoglobin in your urine, which can turn it dark or reddish. Many people with PNH don’t have discolored urine, which is just one of many possible symptoms of the condition.

Signs and Symptoms of PNH

While PNH is named after the symptom of dark or reddish urine, not everyone will develop this symptom. Discolored urine is often seen in the morning, due to the concentration of urine overnight (hence the word “nocturnal” in PNH).

Mild hemolysis in PNH can also lead to the following symptoms:

• Fatigue
• Shortness of breath
• Rapid heartbeat
• Headaches
• Chest pain
• Back pain
• Difficulty breathing, especially during physical activity

Severe hemolysis in PNH can include these additional symptoms:

• Severe, disabling fatigue
• Difficulty swallowing
• Painful spasms in your abdomen or affecting your esophagus
• Erectile dysfunction in men

Hemolysis and its symptoms are ongoing in people with PNH but may get worse at times due to stress, infection, or traumatic events.

Paroxysmal nocturnal hemoglobinuria can cause any of these symptoms. Everyday Health

• Sharp pain in your abdomen
• Feeling bloated or full
• Headaches
• Difficulty thinking
• Difficulty breathing
• Heart palpitations (fluttering or pounding heartbeat)

Causes and Risk Factors of PNH

PNH develops when a genetic mutation leads to the production of defective red blood cells. This mutation typically occurs in adults and is not inherited from your parents or passed on to your children.

• When your complement system targets PNH red blood cells, the cells break apart and release hemoglobin (a protein that carries oxygen throughout your body) into your blood. Hemoglobin that is not in red blood cells is called free hemoglobin. PNH disrupts the body’s ability to clear excess free hemoglobin, which can lead to kidney dysfunction.
• If the rate of red blood cell destruction (hemolysis) is greater than the rate at which your body produces new red blood cells, you can develop anemia, which is an inadequate number of red blood cells.
• When there is too much free hemoglobin in your blood, your body may try to clear it out by releasing a substance known as nitric oxide, depleting your body’s supply of nitric oxide in the process. This depletion can lead to sudden muscle or esophageal spasms.
• Abnormal stem cells in PNH may also develop into abnormal platelets, which can lead to dangerous blood clots in different areas of the body. It’s also possible that red blood cell destruction may contribute to an increased clotting risk.

• Aplastic anemia is a rare disorder in which there is severe bone marrow failure, leading to a very low number of hematopoietic stem cells and, eventually, low levels of red and white blood cells and platelets. Aplastic anemia can cause fatigue, dizziness, headaches, excessive bleeding, or infections.
• Myelodysplastic syndrome (also known as MDS or myelodysplasia) is a group of blood disorders in which red blood cells, white blood cells, and platelets do not develop properly, leading to abnormally low levels of them in your blood. MDS can cause fatigue, dizziness, or abnormal bruising or bleeding.
• Leukemia is a form of cancer that affects your bone marrow and blood, and leads to a buildup of immature blood cells. People with leukemia may have low levels of red or white blood cells or platelets.
• Paroxysmal cold hemoglobinuria (PCH), cold agglutinin disease (CAD), and warm autoimmune hemolytic anemia (WAHA) are forms of autoimmune hemolytic anemia, meaning that the body’s own immune system targets and prematurely destroys red blood cells. These disorders can cause fatigue, dizziness, jaundice (yellowed skin and eyes), or heartbeat irregularities, among other potential symptoms, the Cleveland Clinic notes.

  [5]

How Is PNH Diagnosed?

Diagnosing PNH generally involves recognizing signs of red blood cell destruction (hemolysis) and narrowing the scope of potential causes through blood tests, before finally ordering a test to identify the abnormal red blood cells that define PNH.

• Complete Blood Count This test measures levels of different blood cells and components, including red blood cells, white blood cells, platelets, and hemoglobin.
• Basic Metabolic Panel This test measures levels of various substances in your blood, giving information about processes including kidney function, muscle breakdown, and energy metabolism.

Additional tests may include the following:

• Urine Testing Your doctor may want to look for hemoglobin or excess iron in your urine.
• Reticulocyte Count This blood test measures the level of immature red blood cells (reticulocytes) in your blood. This can help determine if your body is producing enough healthy red blood cells.
• Haptoglobin This protein helps clean up after damaged red blood cells. A low level in your blood may indicate damaged red blood cells.
• Lactate Dehydrogenase A high level of this enzyme, normally found in red blood cells, may indicate a higher than usual level of red blood cell destruction.

On the basis of the results of any of these tests, your doctor may choose to order the main test used to diagnose PNH, known as flow cytometry. This test involves sorting your red blood cells in a specialized machine, which can identify the abnormal red blood cells seen in PNH.

Treatment Options and Medications for PNH

Treatment for PNH falls in two general categories: treating the disease directly, and treating specific problems or complications that arise from the disease.

Medications for PNH

• eculizumab (Soliris)
• pegcetacoplan (Empaveli)
• ravulizumab (Ultomiris)
• iptacopan (Fabhalta)

Approved by the U.S. Food and Drug Administration (FDA) in 2007, eculizumab is the most established treatment for PNH. It is given by intravenous infusion every two weeks. It stops the breakdown of red blood cells and may reduce the risk for blood clots. Because it blocks part of the immune system, eculizumab increases the risk for meningococcal infections. You’ll need to receive a meningococcal vaccine before your first treatment.

Ravulizumab received FDA approval for PNH in 2018. It works similarly to eculizumab but is given by infusion every eight weeks.

Pegcetacoplan gained FDA approval in 2021 to stop red blood cell destruction in PNH. It works in a somewhat different way from the other two drugs, by binding to a protein that’s part of the complement system’s attack on abnormal red blood cells.

In 2023, iptacopan became the first oral medication approved to treat adults with PNH.

Treatment Options for Blood Cell Depletion and Blood Clots in PNH

Before the creation of drugs that can block the complement system from attacking abnormal red blood cells, the main treatment for PNH was blood transfusions to help correct a low blood cell count. Blood transfusions may still be needed for people with PNH who have very low blood cell counts.

Other supportive or symptom-based treatments for PNH may include these options:

• Folic Acid (Folate) Your body may need a supplement to replenish its supply of folate, which may be depleted as a result of extra red blood cell production.
• Supplemental Iron You may become iron deficient because of red blood cell destruction and loss of iron through your urine.
• Steroids While a steroid such as prednisone may slow the destruction of red blood cells, this treatment has limited effectiveness and can cause serious side effects, NORD notes.
• Anticoagulants These drugs help stop blood clots from forming, and they may be beneficial for some people with PNH; however, it’s important to weigh this benefit against the risk of excessive bleeding.
• Thrombolytics Clot-busting drugs may be needed for some people with PNH who develop blood clots, but these drugs carry substantial risks, including the risk of bleeding.

Prevention of PNH

PNH develops because of a genetic mutation that cannot be prevented. But effective treatment for PNH can prevent severe disease and symptoms of the condition, as well as dangerous complications like blood clots or kidney disease.

PNH Prognosis

If your PNH is severe enough to require treatment, you’ll almost certainly need to continue with your treatment indefinitely. You’ll also probably need to follow precautions to help prevent dangerous blood clots, especially if you need surgery or when you travel by air.

Complications of PNH

• Anemia
• Blood clots
• Budd-Chiari syndrome
• Chronic kidney disease

Anemia (inadequate red blood cells) develops when your bone marrow can’t produce enough red blood cells to make up for the abnormal ones being destroyed. Symptoms of anemia may include fatigue, light-headedness, shortness of breath, a fast heart rate, abnormal paleness, or jaundice (yellow cast to your eyes and skin).

People with PNH are about 6 times more likely to develop chronic kidney disease, according to Cleveland Clinic. This is because of the ongoing damage that the kidneys can sustain as a result of removing hemoglobin from the blood.

The Takeaway

• Paroxysmal nocturnal hemoglobinuria is a rare blood disorder caused by a genetic mutation. It’s characterized by the production of defective red blood cells that break apart in the bloodstream.
• There’s no singular or telltale symptom of PNH, but people who have it may experience fatigue, headaches, and trouble breathing, among other serious effects, like blood clots.
• While you cannot prevent PNH, medication and treatment are available to effectively manage the condition and support a long lifespan