PNH - Paroxysmal Nocturnal Hemoglobinuria
The information on this page can help you understand the nature of PNH but it is not a substitute for the advice of your doctor. Always seek medical advice from a qualified physician.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a chronic disease in which the red cells in your blood break apart. PNH occurs when a particular change in a particular gene leaves your blood cells without protection from your own immune system. Your immune system attacks and breaks up your red blood cells, producing two harmful results: (1) your bloodstream has a shortage of functioning red cells, and (2) excess hemoglobin from the broken cells is released into your bloodstream.
- is a rare disease, although the exact number of affected patients is not known. Estimates range from 10,000 to 21,000 people with PNH across North America and Europe, with as many as 1,700 new diagnoses across those regions each year. That equates to about 400 new PNH patients each year in the U.S. and about 80 each year in the U.K., with a total of nearly 5,000 people with PNH in the U.S. and nearly 1,000 in the U.K., based on population estimates from 2010 and 2011.
- is not contagious. You cannot "catch" PNH from exposure to someone with the disease.
- is not hereditary. You cannot inherit it from your parents or pass it on to your children. It is not known if people can have a genetic predisposition to bone marrow failure.
- can appear at any age but is most commonly diagnosed in young adults, with a median age of about 35 to 42 years at diagnosis.
- affects men and women about equally, although some statistics show women are affected up to 20% more often than men.
- may be more frequent in Southeast Asia and in the Far East.
- can be treated in many ways but can be cured only with a bone marrow or stem cell transplant.
Symptoms of PNH
Symptoms of PNH vary from patient to patient, but common symptoms can be categorized as follows:
From a low red cell count (anemia) and/or the break-up of red cells (hemolysis): feeling extremely tired or weak (fatigue); shortness of breath; irregular heartbeat; rapid pulse; dizziness especially when standing up; headaches; coldness in your hands or feet; pale skin (pallor); chest pain; decreased alertness; weight loss; low appetite; and a shortened attention span.
From a low platelet count (thrombocytopenia): bruising; bleeding; and pinpoint red bleeding spots on the skin (petechiae).
From hemolysis and the resulting release of hemoglobin into the circulating blood: dark urine (caused by hemoglobinuria, meaning hemoglobin in the urine); fatigue; jaundice (yellowed skin or eyes) or gallstones from high levels of bilirubin; and blood clots in a vein (thrombosis). Most PNH patients do not exhibit hemolysis at the time of diagnosis but when hemolysis occurs blood clots are the most life-threatening aspect of PNH. Even though the name "paroxysmal nocturnal hemoglobinuria" refers to the sudden and irregular night-time accumulation of hemoglobin in urine, not all PNH patients have dark urine.
From blood clots and the spasms they can produce: pain in the abdomen, back, head, or esophagus (throat area); trouble swallowing (dysphagia); restless leg syndrome (RLS); and impotence in men.
The combinations of symptoms can interact. Anemia can exacerbate problems from blood clots. A low white cell count (neutropenia) and hemoglobinuria can both result in increased susceptibility to infections. In turn, flu, colds, infections, and other illnesses that activate the immune system may trigger increased hemolysis. Infections and hemoglobinuria can both contribute to kidney failure.
A rapid increase in hemolysis and the resulting symptoms of fatigue, pain, and/or dark urine is called a hemolytic crisis and requires consultation with your doctor, who may prescribe bed rest and hydration or hospitalization.
Because some of these symptoms can result from other conditions, a patient who experiences one or more symptoms of PNH does not necessarily have PNH. For the same reason, PNH may not be recognized or diagnosed at first. It is essential to consult a doctor for a professional diagnosis. Low white blood cell counts and/or low platelet counts are not normally symptoms of PNH and may result from another bone marrow failure disease.
Causes and Risk Factors
PNH results from a change (mutation) in a specific gene, called the PIG-A gene, on a stem cell in your bone marrow. It is not yet known why the mutation occurs in some people and not in others.
It is thought that PNH may occur when bone marrow is weakened by another bone marrow disease, e.g., aplastic anemia, since many patients have both, but it could also be the result of previous bone marrow failure that was never severe enough to be diagnosed. Exposure to certain chemicals, including benzene, and certain antibiotics, such as chloramphenicol, may cause the changes in bone marrow cells that lead to PNH. However, in most cases, PNH is idiopathic, meaning that the cause of the disease is unknown.
Over 10% of aplastic anemia patients and 1% to 3% of MDS patients develop PNH. Patients with PNH sometimes develop aplastic anemia. Patients with aplastic anemia or MDS may be screened periodically with a blood test for PNH.
Diagnosis of PNH
When a doctor suspects PNH based on the patient's symptoms, blood tests are used to confirm or dismiss the possibility. A doctor will review the patient's medical history and order a blood sample to measure levels of red cells and other blood cells. The resulting report, called a Complete Blood Count (CBC), will be compared to normal blood counts to identify any counts that may be too low. A technique called flow cytometry will be used to study the proteins on the surface of the white blood cells called granulocytes. PNH is indicated when some or all of the protective proteins (in particular the CD55 and CD59 proteins) are absent. Flow cytometry replaced a previously used test called the Ham test and a sucrose hemolysis test.
Other tests may be done to identify and assess your condition, including checks of your iron level (a ferritin test), your bilirubin level, and a check for the presence of immature blood cells ("blasts") in your blood. Hemolysis can be measured by checking your LDH (lactate dehydrogenase) enzyme level more easily than by checking for hemoglobin in your bloodstream directly.
If a blood clot is suspected, you may receive a CT, MRI, Doppler, or V-Q scan or other lab tests.
To assess the state of your bone marrow the doctor may perform a pair of tests simultaneously: bone marrow aspiration (BMA) and bone marrow biopsy (BMB). The BMA provides information about the presence or absence of abnormal cells in the marrow. The BMB provides information about blood production in the marrow through the examination of the quantity (also knows as the cellularity) and quality of bone marrow cells.
The Mechanism of PNH
In the human body, stem cells in the bone marrow reproduce (clone) themselves to produce a population of stem cells. Stem cells mature into red blood cells, platelets, and white blood cells, all of which enter the bloodstream when they are mature. Red blood cells carry hemoglobin, an iron-rich protein that transports oxygen to the body. Platelets help blood clot.
White blood cells, part of your immune system, destroy "bad" cells: invading or foreign cells like bacteria and viruses, and abnormal cells. A group of proteins called the complement system helps the immune system. These proteins become active when bad cells are detected. It's called the complement system because it complements (completes and supports) the rest of the immune system.
In healthy people red blood cells carry proteins that protect the cells against the complement system. A small percentage of stems cells may have the PIG-A mutation without causing a problem.
In a person with PNH, stem cells with the mutated PIG-A gene on the X chromosome produce PNH-affected red blood cells, platelets, and to a lesser extent white blood cells. Red cells lacking the protective proteins are attacked by the proteins in the complement system, causing them to break up (hemolysis) and producing symptoms listed above.
Blood cells are referred to as Type I cells if they have the normal protective proteins, PNH Type II cells if they are missing some of the proteins, making them partially sensitive to attack by the complement system, and PNH Type III cells if they are missing all of the proteins, making them the most likely to suffer hemolysis.
The hemoglobin released from hemolysis can bind with nitric oxide (NO), causing you to lose NO that normally helps your muscles stay relaxed. With less NO, muscle spasms can produce the symptoms of pain described above. Also, since nitric oxide normally helps keep platelets from "clumping", a shortage of NO can lead to excess platelet clumping/stickiness, which is a possible cause of the blood clots in PNH patients.
Since stem cells reproduce by cloning, the number of stem cells with the PIG-A mutation determines the number of PNH cells in your circulating blood. The percentage of granulocytes with PNH-associated protein deficiencies is called the clone size. Symptoms of PNH may occur with clone sizes as little as 10%. The clone size is an important factor in judging the state of the disease and is a predictor of the chances of a blood clot.
Treatment of PNH
The choice of treatment for PNH depends on a variety of factors, including:
- severity of symptoms
- clone size (see "The Mechanism of PNH" above)
- presence of other serious medical conditions or diseases
- availability of a matched donor for bone marrow or stem cell transplant
There are many approaches to treatment of PNH. The more you learn about the choices, the better you will be able to be a partner with your doctor in making treatment decisions. In milder cases doctors may recommend only regular tests to watch for changes. But PNH can be life-threatening, especially when blood clots occur, and require hospitalization.
Many people live basically normal lives for decades with PNH. Survival times vary greatly and depend on the individual circumstances for each patient, with average survival over all patients being about 15 to 20 years after diagnosis (a number that grows each year with medical advances) and some living much longer than these averages. Life expectancy is shorter for patients who develop blood clots in key areas, or are diagnosed with MDS or acute myeloid leukemia (AML), so stable PNH patients should have bone marrow biopsies at least every 5 years to check for transformation to MDS or AML, and more often if blood or blast counts are changing. One study found spontaneous recovery in over 10% of patients with PNH and 25% of patients surviving for over 25 years, even before drug treatment with eculizumab became available (see "Drugs to Suppress the Complement System" below). When you read statistics about PNH, it is important to remember that statistics apply to groups, not individuals. All patients react to their illness and treatment differently. The likely course of the disease will vary greatly depending on the specific circumstances of a particular patient.
PNH cannot be corrected through dietary changes or supplements because patients do not have healthy bone marrow capable of producing properly functioning red blood cells. However, a good diet is always important and hydration (drinking liquids) is especially important to flush out the byproducts of hemolysis. Doctors may recommend dietary changes and supplements (e.g., folic acid) to lessen symptoms that result from PNH. Talk to your doctor before taking any supplement, including herbal supplements.
Current treatment options include:
- watch and wait — supportive care
- blood or platelets transfusions
- drugs for blood production
- drugs to suppress the complement system
- drugs to lessen blood clots
- bone marrow, stem cell, and cord blood transplants
Watch and Wait — Supportive Care
If you have only mild/tolerable symptoms, your doctor may recommend a watch and wait strategy or supportive care to manage or lessen symptoms rather than try to slow or stop the course of the disease itself. Monitoring your symptoms, performing tests on a regular basis, and giving you transfusions and other treatment only as needed may be sufficient in low-risk cases. Watch and wait is a conscious decision to avoid making things worse when you are living a mostly normal life.
If PNH patients develop gallstones, the stones should be removed promptly. Patients should not wait until gallstones cause problems.
Transfusions replace the red blood cells lost to hemolysis and the iron lost with them. Platelet transfusions can boost a low platelet count. Iron is necessary for the mechanism of red blood cell production. Ironically, hemolysis can cause iron shortages while frequent blood transfusions can cause just the opposite: iron overload. Iron buildup from long-term treatment with transfusions can damage key organs such as the heart and liver. Iron can be removed with drugs called chelators (U.S. trade names Desferal and Exjade) but they can be difficult to administer and hard to tolerate.
Because PNH patients may receive many transfusions, it is recommended that they receive blood that is filtered and irradiated. Filtering removes leukocytes that might otherwise cause allergic reactions. Irradiating inactivates lymphocytes to avoid a buildup of antibodies that could prevent future transfusions from being effective. Filtered blood is also called leukocyte-reduced or leukocyte-depleted. Many patients also believe that patients who receive frequent transfusions should receive fresh (very recently donated) blood because it might sustain them longer; this topic is a subject of debate.
When PNH patients need red blood cell transfusions, there are special guidelines for blood type matching:
- People who need blood because of accidents, surgery, or most diseases other than PNH can receive a red blood cell transfusion from any compatible blood type. For example, someone with the AB blood type can receive blood from an O, A, B, or AB donor.
- PNH patients should receive red blood transfusions from blood donors who have exactly the same blood type, if possible. For example, a PNH patient with the AB blood type should receive blood from an AB donor, if available.
Drugs for Blood Production
Production of blood cells can be increased by the following treatments. A proportion of the newly made red blood cells is likely to be lost due to hemolysis, so PNH symptoms will still be apparent even as red blood cell production increases. The proteins or hormones called growth factors are normal body products that stimulate the production of blood cells.
- Iron pills can stimulate red blood cell production by increasing iron levels. It's especially important for young women with low iron to maintain their iron level.
- Folic acid (manufactured folate) or the folate in food can increase blood cell production.
- Erythropoietin ("EPO" for short, U.S. trade names Aranesp, Epogen, and Procit) is a growth factor that boosts red blood cell production.
- G-CSF (granulocyte colony-stimulating factor) like filgrastim (U.S. trade names include Neupogen) can boost white blood cell counts.
- GM-CSF (granulocyte macrophage colony-stimulating factor) like sargramostim (U.S. trade names include Leukine) can also boost white blood cell counts.
- Male hormones (androgens) are no longer commonly used but can increase red blood cell production.
Drugs to Suppress the Complement System
Eculizumab (U.S. trade name Soliris) is the only drug approved for treatment of PNH by the FDA in the U.S. and the EMEA in Europe. It suppresses the complement system so that red blood cells with the PIG-A mutation are not attacked and destroyed by the complement system despite their lack of the protective protein. It may also reduce the risk of blood clots.
The FDA approved Soliris for PNH treatment in 2007. As a result, PNH outcome and survival statistics from before 2007 reflect the years when fewer treatment options were available.
Soliris is given by IV over a series of weeks and months. If side effects occur they are usually no worse that those of a common cold. When Soliris treatment is ending it is usually done gradually to prevent a build-up of PNH blood cells.
Prednisone is a corticosteroid hormone that can also can reduce hemolysis, apparently by suppressing the complement system. Steroids can have unwanted side effects under long-term use so doctors use Alternate Day Therapy (you take the medicine only every other day).
Drugs to Lessen Blood Clots
Blood thinners reduce the risk of blood clots by lessening or slowing coagulation (lumping) of platelets. They include enoxaparin (U.S. trade name Lovenox) taken by injection, heparin (U.S. trade names Calciparine and Liquaemin) taken by injection or IV, and warfarin (U.S. trade name Coumadin) taken orally.
A protein called tissue plasminogen activator (tPA) can break up existing blood clots when administered promptly after a blood clot.
The chances of blood clots can be reduced with anti-inflammatory pain relievers that act as anticoagulants: aspirin and to a lesser extent ibuprofen (brand names Advil and Motrin). Care must be used since anticoagulants will exacerbate symptoms of low platelets.
Bone Marrow, Stem Cell, and Cord Blood Transplants
Currently, the only option for curing PNH is an allogeneic transplant using bone marrow, stem cells, or cord blood. "Allogeneic" means that the cells come from someone other than the patient. The patient receives bone marrow or stem cells from a family member, unrelated donor, or cord blood unit. In a successful transplant, defective stem cells in the patient's bone marrow are eliminated and new cells from the donor engraft (begin to function in the recipient's marrow) and produce normal blood cells.
The major risks are rejection of the transplant, mortality during the transplant process (while waiting for engraftment the patient may have no immune system), and graft-versus-host disease (GVHD or GVH). GVHD is an acute or chronic condition in which the patient's new immune system tries to reject his or her own tissue.
Because of these risks, transplants are a less good choice for patients who doctors think have only chronic PNH and have a good chance for spontaneous remission. Ironically, most PNH patients are either "too healthy" to risk a transplant or "too sick" (not otherwise healthy) to qualify for a transplant.
Standard transplants begin with chemotherapy and radiation to destroy diseased cells, while mini transplants (non-myeloablative transplants) use lesser or no chemotherapy or radiation, making them more suitable for older patients or those with other health problems for whom the standard transplant conditioning would be unsuitable. Mini transplants may shorten recovery time but have higher relapse rates, or change the balance of risks and benefits in other ways.
To increase the likelihood of a successful transplant and minimize potential complications, the patient needs a donor with a matching tissue type. Human leukocyte antigen (HLA) typing, which looks at proteins on the surface of cells, is used to match patients and donors. This is not the same as testing your blood type; donors don't have to match your blood type.
Many patients find HLA matches among their brothers, sisters, or other close relatives (an identical twin sibling is the ideal donor), but as many as 70% of patients must search for an unrelated donor or cord blood unit. Doctors can search for donors on behalf of their patients in national and international registries, such as the Be The Match Registry operated by the National Marrow Donor Program (NMDP) in the U.S. The percentage of patients who find a family match or a match in the registry is about 50% for caucasian patients, 10% for black patients, and less than 5% for Asian patients.
A MUD transplant is one from a Matched Unrelated Donor. A haploidentical (or "haplo") transplant uses a half-matched donor, typically a sibling, parent, or child or the patient. Haplo tranplants are less than ideal, but may offer an additional choice to patients up to about age 65.
Other transplants involving partially matched (called "mismatched") donors are also possible, depending on the type of mismatch, but such transplants are riskier.
Because it can take time to identify a donor (3 months or longer is common), it is a good idea to explore the possibilities in the patient's family and/or bone marrow registries as soon as aplastic anemia is diagnosed.
A clinical trial is a study conducted to evaluate a promising new treatment or to continue to learn about a current successful treatment.
Each study is designed to answer scientific questions and to find new and better ways to help patients. Clinical trials are important because the research data they provide is the route to safer and more effective treatments for all patients.
Clinical trials involve some risk because the treatments used are less proven than standard treatments. However, they offer some of the best medical care available, provide both the latest and best medical expertise, and patients receive close attention and monitoring. In addition, trials offer consistency in treatment protocols and quality controls that might vary in other settings.
Usually, clinical trials are free-of-charge for the patient, with some facilities even financing travel expenses. Most insurance companies cover treatment received in a clinical trial. Patients should consider participating in a clinical trial only after their doctor has explained the trial's specific purposes, risks, and benefits.
Clinical trials of alemtuzumab (U.S. trade name Campath) are currently of particular interest since there is evidence of a benefit to PNH patients, and it may be more suitable than steroids for patients who relapse.
Coping with PNH
Following a diagnosis of PNH, patients may feel shocked, scared, angry, or even relieved that they finally have a "name" for their condition. Newly diagnosed patients often describe being overwhelmed by trying to understand what PNH is and how it can be treated while their family and work responsibilities continue. PNH is a complicated disease and trying to make sense of the benefits and risks of each possible treatment can add to a patient's burden.
As a rare disease, PNH is unlikely to be familiar to your general practitioner and you are unlikely to know someone else who has the disease.
Here are some steps that will help you feel more in control of your situation:
- Find a hematologist who is an expert in treating PNH. Get a referral from your primary care physician or insurance company. You can also use the Marrowforums Treatment Center Map to find treatment centers in North America.
- Request information from the Aplastic Anemia & MDS International Foundation (AA&MDSIF). Visit their Online Academy. Attend their conferences. If you'd like to talk to another patient or caregiver, ask to speak to one of their Peer Support Network volunteers.
- Contact national patient or support organizations in your country, such as the Aplastic Anemia & Myelodysplasia Association of Canada.
- Learn as much as you can about PNH and its treatments. Learning the basic terminology of PNH will help you understand what you read and communicate with your doctor.
- Keep track of all of your medical information, including symptoms, tests and their results, treatments (including transfusions received), an up-to-date list of your medications, and contact phone numbers, in one place. A computer, a three-ring binder, or even a folder of papers will work; just keep everything together.
- Be an active participant in your care by asking questions of your doctors until you understand the answers, discussing information you collect, and speaking up about anything that concerns you. Bring a written list of questions to each appointment.
- If possible, have a family member or close friend accompany you to medical appointments. They can help you listen, take notes, and make sure you remember to ask your questions.
- Get a second opinion. No doctor with your best interests in mind will object to your confirming your diagnosis and treatment recommendations with another specialist.
- Take advantage of services offered at your treatment center (counselors and social workers, language translators, etc.), support groups in your city, wellness programs of your insurance company, neighborhood support groups, and support offered by religious groups, even if these services aren't specific to bone marrow failure diseases.
- Keep in regular touch with family, friends, and the others closest to you. Don't let relationships falter just because your situation has changed.
- For those in the U.S., join the PNH Registry, managed by Alexion, which collects demographic and clinical data about PNH patients while maintaining patient confidentiality and providing patients and other registrants with ongoing research information.
- Join the PNH Support Group and take advantage of their reference information and chat and forum areas.
- Talk to other patients in the Marrowforums discussion forums.
We hope that after reading this page you will participate in the discussions at Marrowforums and continue to learn about PNH through the experiences of patients, family members, and caregivers who exchange help and support 24 hours a day, every day of the year.