Everything You Need to Know About Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease where changes in stem cells within the bone marrow prompt red blood cells to break apart. This deprives the body of the normal flow of oxygenated blood. As a result, people with this condition often develop symptoms such as intense fatigue and muscle spasms, as well as potentially life-threatening complications, such as blood clots.

The reason people with PNH are at lifelong risk of having red blood cells break apart — a process called hemolysis — is that bone marrow has started producing cells that are missing an outer coating that normally protects them from attack by the immune system. With a key element in the body’s defense system crippled in this way, the body is forced to contend with persistently low levels of hemoglobin, the protein that ferries oxygen around the body.

Who Gets PNH?

While PNH is a very serious condition that requires careful management, the outlook has changed dramatically in recent years. “It’s something people can live a long life with and is not nearly as life threatening as it used to be,” says Robert Alan Brodsky, MD, a professor of medicine and the director of the division of hematology at Johns Hopkins Medicine in Baltimore.

Thankfully, treatments introduced over the past decade have transformed the ability to manage PNH symptoms. “Most people can be rendered either asymptomatic or minimally symptomatic, depending on their condition,” says Dr. Brodsky.

• Fatigue and weakness, sometimes profound
• Trouble breathing or shortness of breath, including having a hard time exercising
• Easy bleeding or bruising (more frequently than expected or following minor injuries)
• The appearance of tiny, flat, red dots on the skin
• Repeated infections and flu-like symptoms, sometimes with fever
• Headaches, sometimes severe, due to blood clots in the veins around the brain
• Problems concentrating and focusing
• Fast or irregular heartbeat
• Loss of appetite
• Muscle spasms, with possible pain in the belly and other areas
• Urine that looks dark red or the color of dark tea — a condition called hemoglobinuria — that tends to appear in the morning and dissipate over the course of the day
• Blood clots (thrombosis), which tend to develop in the belly area — in which case you may notice swelling, pain, and warmth — and the back, although they can develop anywhere

“The biggest thing we fear [in patients with PNH] is blood clots,” explains Carlos de Castro, MD, a professor of medicine at Duke University School of Medicine in Durham, North Carolina.

People who have PNH acquire the PIG-A mutation over time, rather than inheriting it. It’s not clear why the mutation appears in the first place, but because it’s acquired as opposed to inherited, the disease isn’t passed down to your children.

A doctor may perform an exam and order a number of tests to diagnose the condition; one called flow cytometry is the gold standard diagnostic tool for PNH. This laboratory test enables the technician to count the number of cells in a blood sample and tabulate what percentage are missing their protective protein shield to guard against immune system destruction.

Flow cytometry can also calculate “clone size” among red blood cells, which refers to the number of cells vulnerable to destruction due to the way they’re formed.

Other tests that can help in diagnosing PNH include:

• Complete blood count (CBC), which shows how many of each type of blood cell component are present in the blood. People with PNH tend to have lower numbers of red blood cells and hemoglobin.
• Bilirubin test, which calculates how much of this orange-yellow pigment is in your blood. With PNH, the bilirubin level may be high, because the pigment is generated by the destruction of red blood cells.
• Absolute reticulocyte count, which measures how quickly bone marrow produces and releases red blood cells called reticulocytes. The number rises when the cells are eliminated before they should be.
• Lactate dehydrogenase (LDH) test, which tabulates the amount of the enzyme LDH in your blood. The numbers tend to run high in the presence of red blood cell destruction.

Your doctor may also run additional screenings and tests, such as:

• Bone marrow biopsy, which takes a tiny sample of bone marrow to learn key things about how well it’s producing blood cells and can confirm a PNH diagnosis
• Iron tests, which detects if iron levels are too high or too low, indicating if issues other than PNH are at play
• Erythropoietin (EPO) levels, which could signal a problem other than PNH
• Vitamin B12 levels, which may help shed light on other causes of anemia

Because PNH is so challenging to diagnose, it’s important to find a specialist, such as a hematologist, to help confirm the diagnosis and rule out other conditions. If there’s no hematologist who treats PNH near you, you can apply for assistance from the PNH Patient Travel Assistance Fund to help cover travel costs to and from appointments with a specialist.

Watchful waiting If your blood counts aren’t too low and symptoms aren’t affecting your quality of life, your doctor may simply recommend monitoring your blood counts for changes.

Living a healthy lifestyle If you don’t have many symptoms or complications from PNH, your doctor may suggest you live a healthy lifestyle and take some dietary supplements containing iron and folic acid to help your body ramp up red blood cell production. Your doctor may also recommend avoiding medicines, such as oral contraceptives, that can raise the risk of blood clots.

Blood transfusions With a transfusion, blood or parts of blood from a donor are infused into your body, which can help if your blood count is low. In the past, blood transfusions were common for people with PNH, though fewer people need them today, as newer treatments help maintain your blood count, preventing severe anemia.

Immunosuppressive therapy This approach has also been used to prevent the immune system from attacking bone marrow. Options include antithymocyte globulin and cyclosporine.

Monoclonal antibody medicines There are three drugs specifically designed to treat PNH. The FDA approved the first drug, eculizumab (Soliris), in 2007. It works by reducing activity in the body’s complement system — a part of the immune system — and lessening the risk of blood cell destruction (hemolysis). Ravulizumab-cwvz (Ultomiris) was approved in 2018 and, like eculizumab, works in part by inhibiting the C5 protein, which is involved in the complement system. Both are administered by infusion.

These treatment options have been a game changer for people with PNH. “Most people can be rendered either asymptomatic or minimally symptomatic, depending on their condition,” says Brodsky.

“About 80 to 85 percent of patients can become entirely free of blood transfusions with these drugs,” he adds. “What’s so powerful about them is that they stop the leading cause of death from PNH. Without these drugs, these patients used to clot. But with these drugs, the risk of clotting is about the same as [the control group in their age bracket].”

Targeted C3 inhibitor In May 2021, the FDA approved pegcetacoplan (Empaveli), adding another treatment option for PNH. Pegcetacoplan inhibits C3, a different protein in the complement system.

This medication blocks activation of the complement system at an earlier stage and may be able to block the small fraction of low-level hemolysis that escapes C5 inhibitors, explains Shruti Chaturvedi, MBBS, an assistant professor of medicine at Johns Hopkins Medicine in Baltimore.

“It works above where eculizumab and ravulizumab-cwvz work,” adds Ilene C. Weitz, MD, an assistant professor of clinical medicine at the Keck School of Medicine at the University of Southern California. According to Dr. Weitz, the study mentioned in the FDA approval, which was published in March 2021 in The New England Journal of Medicine, found that pegcetacoplan “lessens blood-cell destruction in PNH and increases hemoglobin, which can improve quality of life.”

Pegcetacoplan can be injected by a doctor or self-administered.

Bone marrow or stem cell transplant If you have severe PNH symptoms, your doctor may recommend either bone marrow or stem cell transplants, which involve replacing bone marrow or stem cells with those from a donor. While it’s the only potential cure for PNH, it comes with risks and isn’t the best option for everyone.

Clinical trials If you’ve tried a number of therapies and still have trouble controlling your PNH, your doctor may talk to you about enrolling in a clinical trial, which would give you access to upcoming promising PNH treatments.

To ensure you’re being treated properly, it’s important to see a PNH specialist — or at least a hematologist — for treatment. These specialists are more likely to be familiar with this rare illness and stay on top of advances in treating and managing PNH.

What’s the Prognosis for People Who Have PNH?

With the introduction of more effective treatments for PNH over the past decade or so, people with this serious blood condition are feeling better and living longer than ever before. In fact, with careful disease management, it’s possible that people with PNH will soon live as long, on average, as those without the condition, says Brodsky.

And there’s more potential good news coming down the pike. “There are newer complement inhibitors that haven’t been approved yet, that are in late-stage clinical trials,” Brodsky says, and will likely be approved in 2021 or 2022.

“These newer medications that are in clinical development may be as good as or better than what’s available now,” he adds, noting that some of these new agents may be available administered under the skin or even orally, compared with the currently available monoclonal antibody medications, which are infusions.

The Aplastic Anemia & MDS International Foundation (AAMDS) offers a number of resources for people with PNH:

• Find a specialist Set up as an interactive map of bone-marrow-failure specialists nationwide, you can use this tool to find doctors near you who know about PNH and how best to treat it.
• Patient educators Call for answers to your PNH questions and guidance on understanding and managing the illness by calling 1-800-747-2820 or emailing help@aamds.org.
• PNH support networks Connect with others who are living with PNH to share your stories and learn from each other’s experiences.

The National Organization for Rare Disorders offers expert information about PNH and runs a patient assistance program that helps people living with the condition and their families. Call 1-855-567-3814 or email pnh@rarediseases.org for more information.