What Is Paroxysmal Nocturnal Hemoglobinuria?

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, potentially life-threatening disorder that causes the red blood cells to break apart (hemolysis), releasing hemoglobin into the urine (hemoglobinuria) and turning it dark or blood-colored. Originally, the disease was thought to occur in bursts (paroxysms) and only at night (nocturnal), but it has since been discovered that the hemolysis is a constant process, occurring throughout the day. 

People with paroxysmal nocturnal hemoglobinuria are at risk of developing blood clots in veins (thrombosis) and bone marrow dysfunction, which leads to a deficiency in the production of all types of blood cells (deficient hematopoiesis). Not everyone with PNH will experience these to the same degree, nor will they exhibit the same symptoms of the disease, of which there are many. PNH is diagnosed mainly through blood testing and can be managed with medications and blood transfusions. The only potential cure for PNH is a bone marrow transplant.

Types of Paroxysmal Nocturnal Hemoglobinuria

PNH affects both males and females of all ethnic backgrounds and may occur at any age, with the median age at diagnosis being in the 30s.

The disease has three main subtypes: 

  • Classical PNH, in which the disease is present in the absence of another bone marrow disorder
  • PNH in the context of other primary bone marrow disorders, such as aplastic anemia or myelodysplastic syndrome (a group of bone marrow diseases that can develop into acute myeloid leukemia)
  • Subclinical PNH, in which there are no symptoms, but bloodwork for another reason may show evidence of the disease

PNH was previously called Marchiafava-Micheli Syndrome.

Symptoms

Symptoms of PNH correlate with the three main characteristics of the disease (hemolysis, thrombosis, deficient hematopoiesis). Here are the symptoms which may accompany each one:

Hemolysis

  • Cola-colored or bloody urine (hemoglobinuria) that can occur throughout the day, and is often darker in the morning
  • Anemia (low red blood cell count)
  • Fatigue
  • Headaches
  • Irregular heartbeat
  • Muscle spasms
  • Erectile dysfunction

Thrombosis

Symptoms are determined by where the blood clot occurs. If the clot is located in a vein of the liver, there may be jaundice and an enlarged liver. In the abdomen, a clot would cause abdominal pain; in the head, a headache, or dizziness. Clots in the skin cause raised, painful, red lumps over large areas of the skin, such as the back.

Deficient Hematopoiesis

  • Susceptibility to infections
  • Fatigue
  • Abnormal bleeding
  • Mouth sores
  • Dizziness
  • Pallor
  • Rapid heartbeat
  • Difficulty breathing

Causes

Paroxysmal nocturnal hemoglobuiaria is caused by a gene mutation in the PIGA gene, but it is not an inherited disease. The gene occurs randomly in a single stem cell, which then multiples and expands, causing the disease. The reason why PNH cells expand and multiply is not fully understood, but a likely cause is that bone marrow failure due to an autoimmune response is at the heart of it.

PNH occurs in most people who are diagnosed with acquired aplastic anemia, a serious disease in which the bone marrow fails to make enough red blood cells, white blood cells, and platelets. 

More than 10 out of every 100 people with aplastic anemia will develop PNH. On average, two out of 100 people with PNH go on to develop myelodysplastic syndrome (MDS). 


Diagnosis

If you experience dark-colored urine, or other symptoms associated with PNH, your doctor may recommend you undergo testing. Diagnosing PNH can be difficult because it is a rare disease with symptoms that overlap with other bone marrow disorders. Testing for PNH includes:

Blood Tests

  • A complete blood count (CBC) measures how many of each blood cell type are in your blood sample
  • An LDH test looks at the level of an enzyme called lactate dehydrogenase. High levels of LDH in the blood can indicate hemolysis.
  • A bilirubin test measures the total amount of this substance in your blood. High levels may indicate the destruction of red blood cells.
  • A reticulocyte count measures the number of young red blood cells in your blood.
  • An erythropoietin (EPO) test measures how much of this protein is being made by your kidneys.
  • A ferritin test checks the level of iron in your blood.
  • Vitamin B12 and folate level test may be done to rule out other causes of low red cell counts.

Flow Cytometry

A flow cytometry test is considered the gold standard for diagnosing PNH. This is a sophisticated blood test that can separate and analyze various components of the blood and reveal whether two key proteins, called CD55 and CD59, are missing from the surface of blood cells.

Bone Marrow Test

In a bone marrow test, a hollow needle is used to remove liquid bone marrow from the pelvic bone. The sample will then be examined under a microscope to look at how well the marrow is producing blood cells.

Only about 500 people in the United States are diagnosed with PNH per year.

Treatment

Treatments for PNH are not curative, but can serve to manage the disease and/or treat specific symptoms. Treatments include:

  • Oral medications: These two drugs are the mainstay of treatment for managing PNH. Ultomiris (avulizumab-cwvz) works by inhibiting the key C5 proteins involved in the disease; Soliris (eculizumab) works by halting the breakdown of red blood cells.
  • Immunosuppressant medications: These are used to keep the immune system from attacking the bone marrow and include antithymocyte globulin (ATG) and cyclosporine.
  • Blood transfusions: With a blood transfusion, components of blood from a donor are infused into your bloodstream to restore low blood counts.
  • Growth factors: These are naturally-occurring hormones that stimulate your bone marrow to make more of certain types of blood cells.
  • Folic acid: Also called folate or vitamin B-12, folic acid helps your bone marrow produce blood cells. Most people get enough folate in their diet. But if you have PNH, you may be prescribed a folic acid supplement as well.
  • Blood thinners: Blood thinners such as Coumadin (warfarin) may be used to reduce the development of blood clots.

The only potential cure for PNH is a bone marrow transplant. With this, your own stem cells are removed from your bone marrow and replaced with healthy bone marrow from a donor. Bone marrow transplants are serious and risky procedures and are only recommended for people with severe PNH disease with repeated formation of blood clots.

Prognosis

The course and severity of PNH varies from person to person. It is possible to have a normal lifespan with milder cases of the disease. Those with PNH as well as aplastic anemia or myelodysplatic syndrome are likely to have a shorter lifespan. 

The main cause of severe complications and death in people with PNH is thrombosis. 

Coping

Living with paroxysmal nocturnal hemoglobinuria requires taking certain precautions. Some things to consider include:

Air Travel and High Altitudes

The farther you get from sea level—for example on a mountaintop or while flying in an airplane—the less oxygen there is. If you have anemia, this shortage can cause chest pain and fatigue. Before you travel by air or visit a location at a high altitude, inform your doctor, who may want to check your red cell count and modify any treatments to prevent a reaction. While flying, it's important to drink plenty of water and move your legs or walk around the cabin to prevent blood clots.

Vaccinations

If you have PNH, you may be more prone to viral and bacterial infections. There have been reports of PNH patients having bad reactions to flu shots, so it's important to talk to your doctor, who can help you weigh the risks and benefits of receiving the vaccine. Your physician can also recommend any other vaccinations that may be advised.

Pregnancy

Having PNH can put both the mother and baby at risk. Risks to the mother include blood clots, preeclampsia, and a need for blood transfusions. Blood-thinning medications such as warfarin reduce the likelihood of clots, but these are not safe to use in the first trimester.

Risks to the baby include prematurity, low birth weight, stillbirth, and delayed growth and development. If you are a woman who is considering pregnancy, it's important to find an obstetrician who specializes in high-risk births.

Surgery

Surgery can increase your risk of blood clots and cause serious bleeding if you have PNH. Your physician may advise you to have a platelet transfusion prior to surgery and prescribe a blood thinner to take after the procedure.

Support

Coping with a serious chronic disease not only takes a physical toll, but an emotional one as well. Resources such as those provided by the AAMDS Foundation can help you find specialists, support groups, social workers, advocacy opportunities, and financial help.

A Word From Verywell

While a diagnosis of paroxysmal nocturnal hemoglobinuria can be frightening, there are more treatments than ever before that are increasing life expectancy, and research on the disease continues. If you are interested, the National Organization for Rare Diseases can provide information on participating in a clinical trial.

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