We're celebrating
40 years!
Last updated:
January 05, 2023
Years published: 1989, 1994, 1996, 1997, 2003, 2004, 2005, 2007, 2011, 2014, 2016, 2019, 2023
NORD gratefully acknowledges Charles J. Parker, MD, Professor of Medicine, Division of Hematology and Hematologic Malignancies, Spenser Fox Eccles School of Medicine at the University of Utah, for assistance in the preparation of this report.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which red blood cells break apart prematurely. It is an acquired hematopoietic stem cell disorder. Hematopoietic stem cells are created in the bone marrow, the spongy center of the long bones of the body. These cells grow and eventually develop into red blood cells, white blood cells and platelets. Some hematopoietic stem cells in individuals with PNH are defective and consequently produce defective blood cells. These defective red blood cells of PNH are extremely susceptible to premature destruction by a particular part of a person’s own immune system called the complement system. The destruction of red blood cells (hemolysis) by complement leads to episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich, oxygen-containing pigment of the blood. Individuals with hemoglobinuria may exhibit dark-colored or blood colored urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. However, hemolysis in individuals with PNH is a constant process (i.e., it does not occur only at night). Hemoglobin in the urine may not always be visible. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly from one person to another and affected individuals usually do not exhibit all the symptoms associated with the disorder.
The symptoms of PNH occur because of the production of defective blood cells and because the bone marrow does not produce enough blood cells. The specific symptoms and progression of the disorder vary greatly from one person to another. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to cause life-threatening complications.
It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The premature destruction of red blood cells (hemolysis) is the primary clinical finding associated with PNH. Hemolysis may result in hemoglobin in the urine, although many individuals with hemolysis do not have visible hemoglobin in the urine. When hemolysis occurs, a red blood cell’s outer wall (membrane) breaks down (lysis) releasing hemoglobin. Hemoglobin is excreted from the body in the urine, resulting in the dark-colored or blood colored urine (hemoglobinuria) that is characteristic of this disorder. Hemolysis is ongoing, but may worsen (i.e., a person may have a hemolytic episode) during periods of infection, trauma or stress. The premature destruction of red blood cells may result in low levels of circulating red blood cells (hemolytic anemia) that is made worse by the underlying bone marrow dysfunction.
Chronic hemolysis is central to all the symptoms and physical findings associated with PNH. Mild hemolysis can cause fatigue, rapid heartbeat, headaches, chest pain and difficulty breathing when exercising. If hemolysis is severe, additional symptoms can develop, including disabling fatigue, difficulty swallowing (dysphagia) and painful contractions that affect the abdomen, the esophagus (esophageal spasms) and, in men, can cause erectile dysfunction and impotence. Chronic hemolysis can also lead to the development of blood clots and some affected individuals may develop acute and chronic kidney (renal) disease.
Approximately 15-30 percent of individuals with PNH develop blood clots, especially in the veins (venous thrombosis). The exact reason individuals with PNH develop blood clots is not fully understood. In addition to red blood cells, defective hematopoietic stem cells may also produce defective platelets. Some researchers believe that these defective platelets are abnormally prone to forming blood clots. Chronic hemolysis may also contribute to the development of blood clots. Blood clots can be carried via the bloodstream to various areas of the body, potentially resulting in life-threatening complications. Blood clots may reduce or cut off blood flow to various organs, especially the stomach, liver, and brain. The specific symptoms associated with venous thrombosis depend upon the specific area of the body affected. For example, blood clots affecting the liver may result in jaundice, abdominal pain, or, potentially, a condition known as Budd-Chiari syndrome (for more information, see the Related Disorders section below). Blood clots affecting the stomach and bowels may result in a sharp pain in the abdomen or a bloated or full feeling. Blood clots affecting cerebral veins may cause symptoms such as headaches or problems with cognition (thinking). Blood clots in the lungs can result in shortness of breath, difficulty breathing and heart palpitations. In rare cases, blood clots may form in the arteries. Blood clots can potentially cause life-threatening complications by cutting off blood flow to vital organs.
All patients with PNH have some degree of bone marrow dysfunction. Individuals with mild bone marrow dysfunction may not have any symptoms or only mild symptoms. Individuals with severe bone marrow dysfunction may have low levels of red and white blood cells and platelets (pancytopenia). Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is known as anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.
Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea) and cardiac symptoms, including chest pain. Individuals with leukopenia have an increased risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Women may develop increased menstrual blood loss (menorrhagia).
Many individuals with PNH may simultaneously have another, closely related disorder known as acquired aplastic anemia. To a lesser extent, some individuals may have myelodysplasia. Although the exact relationship among these disorders is unknown, researchers now believe that PNH arises from autoimmune bone marrow failure, which is the cause of most cases of acquired aplastic anemia and some cases of myelodysplasia. In rare cases, PNH may eventually develop into acute leukemia. The reason for this transformation is unknown. (For more information on these disorders, see the Related Disorders section below.)
Two factors are necessary for the development of PNH: an acquired somatic mutation of the PIGA gene, which affects one or more hematopoietic stem cells creating defective “PNH” blood cells, and a process that leads to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while healthy stem cells are destroyed, resulting in the development of PNH. The reason that defective cells survive while healthy cells are destroyed is incompletely understood but appears to be due to properties of the PNH cell that provide a survival advantage in the setting of immune-mediated attack on the bone marrow.
The mutation in the PIGA gene is a somatic mutation, which means that it occurs after conception; it is not inherited and is not passed on to children. This mutation occurs randomly, for no apparent reason (sporadically). In PNH, this mutation occurs in a single hematopoietic stem cell (clonal disorder), which then multiplies and expands. The reason why PNH cells expand and multiply is not fully understood. Researchers believe that other factors such as secondary gene mutations or immune factors may be necessary for PNH cells to expand and multiply. Therefore, although the PIGA mutation is necessary for the development of PNH, its presence alone is not sufficient to cause the disorder. In a few cases, this additional factor has been shown to be a second somatic mutation (other than PIGA) that gives the mutant cell a growth advantage.
The PIGA gene produces a protein that is essential to the creation (biosynthesis) of glycosyl phosphatidylinositol (GPI) anchors. These anchors allow some proteins to attach to a cell’s membrane. These proteins are called GPI-anchored proteins. In cells with a PIGA gene mutation, the GPI anchors are not formed, and, consequently, GPI-anchored proteins cannot attach to the cells’ membranes. Some of these GPI-anchored proteins serve to protect cells from the immune system. Consequently, a lack of these surface proteins renders “PNH” blood cells extremely susceptible to destruction by a part of the immune system known as the complement system.
The complement system is a complex group of proteins that work together to fight infection in the body. These proteins respond to bacteria, viruses or other foreign substances in the body. They work with white blood cells to destroy foreign material in the body. In individuals with PNH, the complement system mistakenly destroys “PNH” blood cells due to the lack of GPI-anchored proteins that normally protect blood cells from the activity of the complement system.
PNH is believed to affect males and females in equal numbers, although some studies show a slightly more females affected. The prevalence is estimated to be between 0.5-1.5 per million people in the general population. The disorder has been described in people of many ethnic backgrounds and has been identified in all areas of the world. The disorder may occur with greater frequency in individuals from Southeast Asia or the Far East who experience greater rates of aplastic anemia. The disorder can affect any age group. The median age at diagnosis is during the 30s.
PNH was first reported in the medical literature in the latter half of the 19th century. The disorder was termed paroxysmal nocturnal hemoglobinuria because of the mistaken belief that hemolysis and subsequent hemoglobinuria occurred only in intermittent episodes (paroxysmally) and with greater frequency during the night (nocturnal). However, while hemoglobinuria may appear paroxysmally, hemolysis is ongoing both during the day and at night.
A diagnosis of PNH may be suspected in individuals who have symptoms of intravascular hemolysis (e.g., hemoglobinuria, abnormally high serum LDH concentration) with no known cause. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. The main diagnostic test for individuals with suspected PNH is flow cytometry, a blood test that can identify PNH cells (blood cells that are missing GPI-anchored proteins).
Treatment
The treatment of PNH is directed at the specific symptoms that are present in each individual and includes a variety of different therapeutic options.
In 2007, the U.S. Food and Drug Administration (FDA) approved eculizumab (Soliris) as a treatment for PNH. This is the first drug to be approved for this disorder. Eculizumab does not cure PNH but halts the breakdown of red blood cells and can reduce the risk of thrombosis and improve overall quality of life. Eculizumab works by blocking the complement system of the body that inadvertently destroys PNH red blood cells. Because it blocks part of the body’s natural immune system, eculizumab increases the risk of meningococcal infections. Therefore, patients must be vaccinated with a meningococcal vaccine at least two weeks prior to receiving the first dose of eculizumab. In 2009, Canada’s national healthcare regulatory agency, Health Canada, approved eculizumab (Soliris) for the treatment of patients in Canada with PNH.
In 2018, the FDA approved ravulizumab (Ultomiris) for treatment of the hemolysis of PNH. Ravulizumab works in a manner identical to eculizumab and was shown to be clinically non-inferior to eculizumab. Ravulizumab is given every eight weeks, whereas eculizumab is given every two weeks.
In 2021, the FDA approved pegcetacoplan (Empaveli) to treat adults with PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3). Consequently, pegcetacoplan blocks both extravascular hemolysis and intravascular hemolysis, whereas eculizumab and ravulizumab block intravascular hemolysis but not extravascular hemolysis. Patients who remain anemic (particularly if transfusions are required) due to extravascular hemolysis despite treatment with eculizumab or ravulizumab may benefit from treatment with pegcetacoplan. Pegcetacoplan is given as a self-administered subcutaneous infusion two or in some cases, three times per week.
Additional treatment for PNH is symptomatic and supportive and varies depending upon the individual’s age, general health, presence of associated disorders, severity of PNH and degree of underlying bone marrow failure.
Some individuals with PNH receive folic acid (folate) supplements to ensure that the supply of folate is adequate as demand increases when the bone marrow attempts to compensate for the hemolytic anemia of PNH by augmenting red blood cell production (erythropoiesis) in the bone marrow. Supplemental iron should be given to individuals with iron deficiency, which can occur because of red blood cell destruction and the consequent loss of iron in the urine.
Some physicians suggest that individuals exhibiting symptoms of hemolysis should receive treatment with steroids such as prednisone because it is believed that such treatment slows the rate of destruction of red blood cells. However, treatment with steroids such as prednisone is controversial because steroid therapy is not beneficial to everyone and carries the potential for serious side effects, especially if the therapy is continued for a long duration.
The administration of drugs that block the formation of blood clots (anticoagulation therapy) may be prescribed. Some individuals may be placed on long-term anticoagulant therapy. Use of blood thinners must be strictly managed because of the risk of excessive bleeding due to low platelet numbers in some individuals.
Individuals with Budd-Chiari syndrome may be treated by thrombolytic therapy, in which certain drugs are used to breakdown or dissolve blood clots. Such treatment requires experience in managing the potential side-effects these drugs as the risk of adverse events (particularly bleeding) is substantial.
The only curative therapy for individuals with PNH is bone marrow transplantation. However, because of the risk of morbidity and mortality, it is reserved for individuals with serious complications such as severe bone marrow failure or repeated, life-threatening blood clot formation. The specific form of bone marrow transplantation used most often in treating PNH is an allogeneic bone marrow transplant. During an allogeneic bone marrow transplant, an affected individual’s bone marrow is destroyed usually by chemotherapy, immunotherapy, radiation or some combination and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted intravenously into the body where it travels to the bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is a sibling with an identical HLA type. However, in some individuals, a search for an unrelated, matched donor is necessary. Bone marrow transplantation can cure underlying bone marrow dysfunction and can eliminate the defective PNH stem cells.
Drug treatments for the hemolysis of PNH have no effect on the underlying bone marrow dysfunction that affects many people with PNH. Individuals who have severe bone marrow failure may be treated with immunosuppressive therapy. Individuals with acquired aplastic anemia have responded favorably to this form of treatment, in which certain drugs are used to suppress the activity of the immune system. This form of treatment may be beneficial in cases of PNH that are dominated by bone marrow failure. While the immunosuppressive therapy can restore bone marrow function, it does not eradicate the PNH clone. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG), cyclosporin and eltrombopag.
Some individuals with PNH with low blood cell counts may receive treatment with blood transfusions. This treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding and antibiotics to treat or prevent infections. Affected individuals who are eligible for a bone marrow transplant should not, if possible, receive blood transfusions because blood transfusions reduce the chances of a successful transplant.
Some individuals with PNH may receive treatment with manmade (synthetic) growth factors. Growth factors are proteins normally found in the body that stimulate the bone marrow to produce blood cells. Erythropoietin (EPO) is a growth factor produced by the kidneys that stimulates the bone marrow to create red blood cells. Epogen, Procrit and Aranesp are forms of erythropoietin. Therapy with red blood cell growth factors may lessen the need for blood transfusions.
Individuals with PNH who have low levels of white blood cells may receive growth factors such as granulocyte-colony stimulating factor (G-CSF) that stimulate the bone marrow to make granulocytes (a type of white blood cell that fights bacterial infections).
Some individuals with PNH may receive treatment with androgens, which are male hormones that stimulate the bone marrow to produce red blood cells. Androgen therapy, such as danazol, may help to improve the symptoms of anemia.
A number of new complement inhibitors for treatment of PNH are undergoing clinical trials in humans. Some of these new therapeutic agents work like eculizumab and ravulizumab by blocking the 5th component of complement and some inhibit complement at other sites.
Iptacopan has received FDA breakthrough designation for treatment of PNH and has recently shown favorable efficacy and safety results in a phase III study compared to eculizumab or ravulizumab in PNH patients with residual anemia. Iptacopan is an oral inhibitor of complement factor B (fB), an essential component of the alternative pathway of complement (the part of the complement system that initiates hemolysis of PNH red blood cells).Therefore, by blocking factor B, complement activation on PNH erythrocytes is inhibited, preventing both extravascular and intravascular hemolysis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about paroxysmal nocturnal hemoglobinuria:
Charles J. Parker, MD
Professor of Medicine
Division of Hematology and Hematologic Malignancies
University of Utah School of Medicine
email: Charles.Parker@hsc.utah.edu
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Parker CJ, Ware RE. Paroxysmal Nocturnal Hemoglobinuria. In: Wintrobes Clinical Hematology, 14th ed. Greer JP, Rodgers GM, Glader B, et al., eds. 2019 Wolters Kluwer. Philadelphia, PA. pp. 783-822.
Parker CJ. Paroxysmal Nocturnal Hemoglobinuria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:389-390.
JOURNAL ARTICLES
Parker, CJ. Update on the diagnosis and management of PNH. Hematology Am Soc Hematol Educ Program. 2016; 208-16. https://www.ncbi.nlm.nih.gov/pubmed/27913482
Luzzatto L. Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria. F1000Res. 2016;F1000 Faculty Rev-209. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765720/
Loschi M, Porcher R, Barraco F, et al. Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study. Am J Hematol. 2016;91:366-370. https://www.ncbi.nlm.nih.gov/pubmed/26689746
DeZern AE, Brodsky RA. Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. Hematol Oncol Clin North Am. 2015;29:479-494. https://www.ncbi.nlm.nih.gov/pubmed/26043387
Devalet B, Mullier F, Chatelain B, Dogne JM, Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. Eur J Haematol. 2015;95:190-198. https://www.ncbi.nlm.nih.gov/pubmed/25753400
Parker CJ. Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 2012;19:141-148. https://www.ncbi.nlm.nih.gov/pubmed/22395662
Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low level extravascular hemolysis occurring through C3 opsonization. Haematologica. 2010;95:567-573. https://www.ncbi.nlm.nih.gov/pubmed/20145265
Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009;113:6522-6527. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710914/
Brodsky RA. Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2008;22:65-74. https://www.ncbi.nlm.nih.gov/pubmed/18063459
Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria. Br J Haematol. 2007;137:181-192. https://www.ncbi.nlm.nih.gov/pubmed/17408457
Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-1243. https://www.ncbi.nlm.nih.gov/pubmed/16990386
Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:3699-3709. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895106/
Meyers G, Parker CJ. Management issues in paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2003;77:125-132. https://www.ncbi.nlm.nih.gov/pubmed/12627847
ABSTRACT
De Latour RP, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety in patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multicenter, phase III APPLY-PNH study. Late-breaking abstract presented at: Annual Meeting of the American Society of Hematology; December 2022). https://ashpublications.org/blood/article/140/Supplement%202/LBA-2/493431/Oral-Monotherapy-with-Iptacopan-a-Proximal
INTERNET
Paroxysmal Nocturnal Hemoglobinuria. Genetics Home Reference. Last updated February 24, 2022. Available at: https://ghr.nlm.nih.gov/condition/paroxysmal-nocturnal-hemoglobinuria Accessed Jan 5, 2023
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/