Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which your body produces defective red blood cells that break apart in your bloodstream. This premature destruction of red blood cells can lead to symptoms including fatigue, headaches, and difficulty breathing.
PNH develops because of a genetic mutation that affects your body’s production of blood cells. It develops after birth and is not passed from parents to their children. PNH is diagnosed based on your symptoms and a variety of blood tests, which can identify the consequences of red blood cell destruction as well as the actual abnormal red blood cells.
Newer treatments for PNH have dramatically changed the outlook for people with the condition, who can now typically expect to live as long as people without PNH, according to the Cleveland Clinic. But people with PNH still need to look out for dangerous complications, particularly blood clots that can affect many different areas of the body.
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
Symptoms of PNH can vary widely from one person to the next, and most people with PNH don’t have all the symptoms, according to the National Organization for Rare Disorders (NORD). The main symptoms of PNH are related to hemolysis, or the destruction of red blood cells. The nature of your symptoms may depend on the severity of hemolysis.
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:
- Shortness of breath
- Rapid heartbeat
- Chest pain
- Back pain
- Difficulty breathing, especially during physical activity
Severe hemolysis in PNH can lead to the following 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 PNH, but may get worse at times due to stress, infection, or traumatic events.
Some people with PNH develop blood clots as a result of the condition, which can lead to additional symptoms depending on where in your body the blood clot occurs:
- Sharp pain in your abdomen
- Feeling bloated or full
- 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.
The PNH disease process starts in your bone marrow, which produces cells known as hematopoietic stem cells. These cells eventually grow and mature into red blood cells, white blood cells, and platelets. In PNH, a mutation occurs in one of these stem cells, in what’s known as the PIGA gene. This abnormal stem cell then divides over and over to produce many abnormal stem cells, which go on to become abnormal red blood cells.
Many experts believe that the mutation that causes PNH also happens in healthy people, and only leads to disease — with abnormal stem cells multiplying quickly — when people have underlying bone marrow dysfunction. Weakened bone marrow may occur due to aplastic anemia or another bone marrow disease, which may be mild or undiagnosed, according to the Aplastic Anemia and MDS International Foundation (AAMDSIF).
The abnormal red blood cells that develop in PNH — known as PNH red blood cells to differentiate them from your healthy red blood cells — lack a protective shield of proteins. Without this shield, they are vulnerable to attack and destruction by a part of your immune system known as the complement system.
When PNH red blood cells are attacked by your complement system, they break apart and release hemoglobin — a protein that carries oxygen throughout your body — into your blood. When this red blood cell destruction (hemolysis) happens faster than new red blood cells can be produced, it leads to anemia (inadequate red blood cells).
When there is too much hemoglobin in your blood — known as free hemoglobin when it’s not in red blood cells — your body may try to “clean up” this hemoglobin 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.
You’re more likely to develop PNH if:
- You’re between 30 and 40 years old
- You have aplastic anemia or another bone marrow disorder
More than 1 in 10 people with aplastic anemia will develop PNH, according to AAMDSIF. Some people with PNH may also go on to develop aplastic anemia.
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.
In response to your symptoms, your doctor will likely order a couple of widely used blood tests.
- Complete blood count (CBC) This test measures levels of different blood cells and components, including red blood cells, white blood cells, platelets, and hemoglobin.
- Basic metabolic panel (BMP) This test measures levels of various substances in your blood, giving information about processes including kidney function, muscle breakdown, and energy metabolism.
Based on the results of these blood tests or along with them, your doctor may order other tests, Mount Sinai notes.
- 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 (LDH) A high level of this enzyme, normally found in red blood cells, may indicate a higher than usual level of red blood cell destruction.
- Sucrose hemolysis test This test looks at how your red blood cells react to swelling when they are placed in a sugar solution, and can identify fragile red blood cells.
- Ham test This test looks at whether red blood cells become more fragile when they’re placed in an acidic solution.
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.
Duration and Prognosis of PNH
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.
People with PNH face many heightened risks related to pregnancy and childbirth, which means that pregnancy is generally not advised, according to AAMDSIF. These risks include blood clots, preeclampsia (dangerously high blood pressure), premature delivery, low birth weight, and delayed growth and development in your infant.
Even just a couple of decades ago, PNH was a much more debilitating disease with few effective treatment options, and most people lived only about 10 to 20 years following their diagnosis, the Cleveland Clinic notes. There are now effective treatments available that can help prevent serious complications, and you can generally expect to live as long as someone without PNH.
Treatment and Medication Options 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.
Approved Drug Therapies for PNH
The main drug treatments for PNH all work by interfering with the complement system’s attack on abnormal red blood cells, according to NORD:
- Eculizumab (Soliris)
- Pegcetacoplan (Empaveli)
- Ravulizumab (Ultomiris)
Eculizumab is the most established treatment for PNH, and is given by intravenous (IV) infusion every two weeks. It has been shown to stop the breakdown of red blood cells, and may also 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 is a more recently developed drug that is very similar to eculizumab, but is given by infusion every eight weeks instead of every two weeks.
Pegcetacoplan is the most recently approved drug 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.
Treating Blood Cell Depletion and Blood Clots in PNH
Before any drugs were developed to block the complement system’s attack on abnormal red blood cells, the main treatment for PNH was blood transfusions. Blood transfusions may still be needed in cases of PNH involving very low blood cell counts.
Growth factors are another treatment that can help correct a low blood cell count. These drugs work by stimulating your bone marrow to produce more blood cells, and can help reduce the need for blood transfusions. Erythropoietin is the main growth factor for red blood cells. Synthetic versions include epoetin alfa (Epogen, Procrit, Retacrit) and darbepoetin alfa (Aranesp).
One procedure that can actually cure PNH is a bone marrow transplant, which stops the production of abnormal red blood cells. But because of the risks involved, a bone marrow transplant is typically recommended only in cases of severe bone marrow failure or a history of life-threatening blood clots, according to NORD.
Other supportive or symptom-based treatments for PNH may include:
- Folic acid (folate) A supplement may be needed to replenish your body’s supply of folate, which may be depleted by 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 Drugs that help stop blood clots from forming may be beneficial for some people with PNH, but this benefit needs to be weighed 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.
Complications of PNH
If PNH isn’t effectively treated, it can lead to serious complications, the Cleveland Clinic notes. Potential complications of PNH include:
- 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).
If you have severe hemolytic anemia (anemia related to red blood cell destruction), your doctor may recommend a blood transfusion to stabilize your red blood cell count, according to the Cleveland Clinic.
Blood clots develop in 15 to 30 percent of people with PNH, according to NORD — particularly in your veins (venous blood clots). Blood clots can develop in one area of your body, break off, and lodge in another area, cutting off blood flow and potentially causing life-threatening complications. Blood clots in PNH may reduce or cut off blood flow to your stomach or intestines, lungs, liver, or brain, potentially causing a range of unpleasant to life-threatening problems.
Budd-Chiari syndrome is a rare complication that develops when the veins of your liver become obstructed by blood clots. It can cause pain in your upper right abdomen, an enlarged liver, or a buildup of fluid in your abdomen.
People with PNH are about six times more likely to develop chronic kidney disease, according to the Cleveland Clinic. This is because of the ongoing damage your kidneys can sustain when they’re removing hemoglobin from your blood.
Research and Statistics: How Many People Have PNH?
PNH is believed to affect between 0.5 and 1.5 per million people, according to NORD, while the National Library of Medicine estimates the range to be between 1 and 5 per million people. PNH is believed to affect males and females in roughly equal numbers, although some evidence points to a slightly higher risk for females.
It’s unclear whether certain racial or ethnic groups are at higher risk for PNH, which is seen in all areas of the world. It’s possible that people of East or Southeast Asian descent are at higher risk for PNH, since this group is known to be at higher risk for aplastic anemia, NORD notes.
According to an analysis of the International PNH Registry using data through July 2017, 51.6 percent of people with PNH had high disease activity at the time of their diagnosis, and 18.8 percent had a history of major adverse events involving blood vessels. Bone marrow failure was seen in 62.6 percent of participants, impaired kidney function was seen in 42.8 percent, and 61.3 percent required a red blood cell transfusion.
There is ongoing research on the disease process in PNH, which may lead to new treatments for the condition. One key area of interest, according to a research review published in the January 2022 Frontiers in Immunology, concerns why the abnormal stem cells in PNH — which develop into abnormal red blood cells — multiply in such a way that they account for a large share of blood cell production. There is strong evidence, the researchers wrote, that the mutation in the PIGA gene that causes abnormal stem cells does not give these cells any kind of growth advantage. This suggests that some other factor or factors must be responsible for the rapid growth of abnormal stem cells in people with PNH.
A number of different blood disorders share certain similarities with PNH, including similar symptoms, according to NORD.
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.
Resources We Love
The websites of the following organizations offer in-depth information about PNH, along with opportunities to get involved with research or advocacy.
This organization offers a wealth of information and support resources for people with PNH and related blood disorders. If you’ve received a diagnosis of PNH, you can sign up for the Global PNH Patient Registry, an ongoing project that offers researchers access to information about the characteristics of people with PNH.
NORD offers detailed information about PNH, including treatments and ongoing research. In addition to offering educational resources, the organization advocates on behalf of people with rare diseases.
This group offers financial assistance to help cover treatment costs for U.S. residents with PNH and other qualifying diseases. Eligibility for assistance is based on your income, health insurance status, and other factors.