Welcome to the NORD Physician Guide to Paroxysmal Nocturnal Hemoglobinuria (PNH). The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was written by Carlos M. De Castro, III, MD, Professor of Medicine, Duke University School of Medicine and Wendell Rosse, MD, Professor Emeritus of Medicine, Florence McAlister Professor Emeritus of Medicine, Duke University School of Medicine. (see acknowledgements for additional information).
NORD is a nonprofit organization representing all patients and families affected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.
PNH is an acquired hematological disorder that can lead to debilitating and life-threatening complications due to chronic intravascular hemolysis and thrombophilia.
PNH patients are anemic due to intravascular hemolysis and an underlying marrow dysfunction, usually characteristic of aplastic anemia.
Eculizumab, an antibody to the fifth component of complement, can reduce or stop the intravascular destruction of red cells and decrease anemia in PNH patients, but has no effect on the marrow dysfunction.
PNH occurs in all age groups, especially young adults.
What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder of the hematological stem cell, thus involving all blood cells. PNH is a debilitating and life-threatening disorder characterized by chronic intravascular hemolysis and thrombophilia 1,2 and can also occur in the setting of bone marrow hypoplasia characteristic of aplastic anemia. The degree of hypoplasia may vary from subclinical to severe. PNH occurs in all age groups, especially young adults. From the PNH Registry, the average age at diagnosis was 32 years with a range from 3 to 99 years 1. It is chronic; many patients have it for years but there is increased mortality from the disease in that, prior to current therapy, 35% of PNH patients would die within 5 years of diagnosis, despite best historical care (Hillmen, 1995) 3,4,5. Many of the effects of the disease are now treated with an antibody to the fifth component of complement (eculizumab) 6,7,8.
PNH is due to a somatic mutation in a hematopoietic stem cell (HSC) that diminishes or abrogates the function of an enzyme crucial to the synthesis of the glycosylphosphatidylinositol (GPI) anchor 12. This anchor binds proteins to the external surface of the cell and consists of phosphatidylinositol (PI), N-glucosamine, three mannoses, and phosphoethanolamine, to which the carboxyl end of the protein is attached (see Fig 1). The missing step in PNH is that which attaches N-acetylglucosamine to the molecule of PI. The most commonly affected gene is called PIG-A and is found on the X chromosome. In a small amount of cases with GPI anchor deficiency no mutation in the PIG-A gene is present. A case report has been described of a PNH patient with a germline mutation and a somatic mutation in the PIG-T gene, another gene in the GPI anchor synthesis pathway 14.
Because of the defect, the GPI-anchored proteins are missing on the cell surface; at least 20 such proteins are known. They include enzymes (acetylcholinesterase, alkaline phosphatase), receptors (FcγIII, various immunological receptors), and most importantly, two complement defense proteins, CD55 (also called decay accelerating factor) 15 and CD59 16,17. The hemolytic anemia and thrombosis and their consequences appear to be largely if not entirely due to the lack of these two proteins. CD55 (the less important) controls the amplification phase of complement activation while CD59 controls the formation of the terminal membrane attack complex (MAC) that is responsible for piercing the cell membrane to cause cytolysis. Without these controls in place, even minimal activation of complement as part of immune surveillance results in either destruction of the cell (for red cells) or activation (of platelets). Nocturnal hemoglobinuria and paroxysms of hemolysis are due to the greater activation of complement that can occur from nocturnally absorbed liposaccharide or infection, trauma, surgery, pregnancy etc.
The defect begins in a single HSC but the disease is manifest only when a significant portion of hematopoiesis is defective. This involves at least two further factors:
PNH is greatly variable in its severity and presentation. Almost all patients are anemic 1 due to two causes: intravascular hemolysis and relative bone marrow hypofunction of the underlying marrow disorder. The anemia may vary depending upon the severity intravascular hemolysis and relative bone marrow hypofunction. The reticulocyte count is usually elevated and haptoglobin markedly reduced. The chronic intravascular hemolysis is manifested by an elevation of the serum lactic acid dehydrogenase (LDH).
Intravascular hemolysis results in hemoglobinuria which may be more severe at night (hence the name of the disease) and is often paroxysmal with episodes of strikingly dark urine followed by periods of clear urine. Paroxysms may be caused by infection, trauma, surgery and pregnancy but usually the cause is not known. Many patients do not have hemoglobinuria.
Marked acute hemoglobinuria may result in acute renal failure 9. Long-term hemoglobinuria may result in renal dysfunction such as acquired Fanconi’s renal syndrome and renal failure due to iron overload of renal cells. In the initial clinical studies of eculizumab, about two-thirds of all patients have evidence of renal dysfunction 10, and up to 8% to 18% die of renal failure if untreated 3.
Several symptoms accompany the hemoglobinemia including marked fatigue, dysphagia, abdominal pain, shortness of breath, and erectile dysfunction 1 . These symptoms are due to the fact that free hemoglobin binds nitric oxide, thus preventing it from relaxing smooth muscles.
Thromboses may occur in the usual places (deep venous regions of the legs) but are more likely to occur in unusual places 11. Budd-Chiari syndrome (hepatic vein thrombosis) and portal vein thrombosis are relatively common and are manifest by right upper quadrant pain, an enlarged liver, ascites, and esophageal varices. Splanchnic vein thrombosis is manifest as abdominal pain and bowel dysfunction. Splenic enlargement may occur due to venous obstruction by thrombosis. Cerebral veins, dermal veins and unusual deep veins (spermatic, ovarian, and brachial) may be involved. Arterial thrombosis is less common but does occur.
The presence of the underlying bone marrow failure may manifest as hypocellularity of the bone marrow, a reduced reticulocyte count relative to the degree of anemia and/or reduced neutrophil and/or platelet count 12. Because of the cytopenias, patients may be misdiagnosed as having either a myelodysplastic syndrome or aplastic anemia.
PNH is a chronic disease. Spontaneous remissions do occur, usually after a number of years, but these are uncommon 4. The mean life span in several studied Western populations observed before treatment with eculizumab (see Treatment page) was available is 10-15 years from diagnosis 3,4,5. Although it is too early to be certain, there are indications that this treatment greatly improves survival 7,25.
Historically, PNH was diagnosed by demonstration of the complement-sensitive red blood cells 20. Now the diagnosis is made by flow cytometry, using a combination of fluoresceinated antibodies to proteins normally present on the various blood cells. Alternatively, a product of Pseudomonas that binds directly to the GPI anchor that has been fluoresceinated (FLAER) may be used. A recommended protocol has been published 21. These techniques can distinguish the size of the abnormal clone characteristic of PNH.
Cells lacking GPI-linked proteins can be found in normal marrow in very small numbers 22. The diagnosis of subclinical PNH is made if the percentage of abnormal granulocytes is between 0.05% and 5%. Clinical PNH is diagnosed if the clone is larger.
For many years, the treatment of PNH was symptomatic and consisted of iron replacement (much iron is lost through the kidneys), folic acid replenishment, and careful care of infections 2,3,4. Transfusions of red blood cells were and are given as needed, care being taken to deplete the product of neutrophils by filtration or washing. Prednisone was sometimes used but the dose needed was too high to permit daily use.
In 2003, a more specific therapy was introduced – eculizumab 6. This is a humanized monoclonal antibody that binds the fifth component of complement, preventing its activation. In this way, the terminal attack complex that is responsible for the penetration of the membrane and thus the destruction of the cell cannot assemble. It thus functions as CD59 for PNH cells.
The drug, which must be given intravenously every two weeks or so, completely or nearly completely, stops the intravascular destruction of the red cells in PNH. This decreases the anemia and markedly reduces the transfusion requirement of almost all patients 6,7,23. Further, marked reduction in hemoglobinemia abrogates many of the symptoms of which patients complain – “fatigue”, dysphagia, abdominal pain, erectile dysfunction, and dyspnea. It appears to ameliorate the renal dysfunction but may not reverse all the damage to the kidneys 8.
Eculizumab appears to reduce the incidence of thrombosis as well, presumably by reducing the activation of platelets by complement 9. Concurrent prophylactic anticoagulation appears to be unnecessary although continued anticoagulation is currently recommended for patients who have had an episode of thrombosis.
The advent of eculizumab has made pregnancy less hazardous for mother and fetus 24. Whereas before it was available, there was a high incidence of thrombosis, maternal death and early birth, this appears to be no longer the case if the drug is started early in pregnancy and is accompanied in the last two trimesters by prophylactic low molecular weight heparin treatment.
Eculizumab appears to be well tolerated and continues to be effective after as long as ten years of use 15. The only apparent side effect is a slightly increased incidence of meningococcal sepsis which may be fatal if not promptly treated. All patients and their health care providers are warned to start appropriate antibiotics when the patient becomes febrile. While it is early to know the effects of eculizumab on long-term survival, two publications would suggest that survival of PNH patients on eculizumab is approaching that of age matched controls 7,25.
Treatment of Marrow Dysfunction in PNH: As noted above, all patients with PNH also have an underlying marrow dysfunction, usually characteristic of aplastic anemia and occasionally that of myelodysplastic syndrome. The degree of dysfunction is highly variable, ranging from subclinical to severe. Eculizumab has no effect on the marrow dysfunction, which must be treated when blood counts are deemed to be life-threateningly low, the same as aplastic anemia however the presence of GPI-AP-deficient PNH clones predicts the response to immunosuppressant in patients with AA. Granulocytopenia and/or thrombocytopenia (in the absence of splenomegaly or thrombosis) may be treated with antithymocyte globulin and/or other immunosuppressant such as cyclosporine 26. When the aplasia is severe, stem cell transplantation may be needed. Since the advent of eculizumab, much of the morbidity and mortality in PNH patients is due to the underlying aplasia and not to PNH itself.
Future Directions
Although much is known about PNH, there is much more to learn in order to control the disease and the underlying marrow dysfunction.
The development of knowledge about PNH shows the results of integrating knowledge obtained in the clinic with that obtained in the research laboratory. It serves as a model for other diseases.
Information on current clinical trials is posted 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 sponsored by private sources, contact: www.centerwatch.com
NORD does not endorse or recommend any particular studies.
1. Schrezenmeier H, Muus P, Socie G, et al., “Baseline characteristics and disease burden in patients in the international paroxysmal nocturnal hemoglobinuria registry,” Haematologica, vol. 99, 2014.
2. Rosse WF, Nishimura J, “Clinical manifestations of paroxysmal noctural hemoglobinuria: Present state and future problems.,” Internat.J.Hematol., vol. 77, pp. 113-120, 2003.
3. Nishimura J, Kanakura Y, Ware RE, et al., “Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan,” Medicine (Baltimore), vol. 83, pp. 193-207, 2004.
4. Hillmen P, Lewiis SM, Bessler M, Luzzatto L, Dacie JV, “Natural history of paroxysmal nocturnal hemoglobinuria.,” N Engl J Med, vol. 333, pp. 1253-1258, 1995.
5. de Latour RP, Mary JY, Salanoubat C, et al., “Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories,” Blood, vol. 112, no. 8, pp. 3099-3106, 2008.
6. Hillmen P, Hall C, Marsh JC, et al, “Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.,” N Engl J Med, vol. 350, pp. 552-559, 2004.
7. Hillmen P, Muus P, Roth A, et al, “Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria,” Br J Haematol, vol. 162, no. 1, pp. 62-73, 2013.
8. Wong EK, Kavanagh D, “Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome,” Transl Res, vol. 165, no. 2, pp. 306-320, 2015.
9. Mooraki A, Boroumand B, Mohammad Zadeh F, Ahmed SH, Bastani B, “Acute reversible renal failure in a patient with paroxysmal nocturnal hemoglobinuria,” Clin. Nephrol., vol. 50, pp. 255-257, 1998.
10. Hillmen P, Elebute M, Kelly R, et al, “Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria.,” Am J Hematol, vol. 83, pp. 553-559, 2010.
11. Hill A, Kelly RJ, Hillmen P, “Thrombosis in paroxysmal nocturnal hemoglobinuria,” Blood, vol. 121, pp. 4985-4995, 2013.
12. Dacie JV, Lewis SM., “Paroxysmal nocturnal haemoglobinuria: variation in clinical severity and association with bone marrow hypoplasia.,” Br J Haematol, vol. 7, pp. 442-457, 1961.
13. Takeda J, Miyata T, Kawagoe K, et al, “Deficiency of the GPI anchor caused by a somatic mutatiomn of the PIG-A gene in paroxysmal nocturnal hemoglobinuria.,” Cell, pp. 703-711, 1993.
14. Krawitz PM, Hochsmann B, Murakami Y, et al., “A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT.,” Blood, vol. 122, pp. 1312-1315., 2013.
15. Nicholson-Weller A., March J.P.; Rosenfeld S.L., Austen K.F., “Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor,” Proc Soc Natl Acad Sci USA, vol. 80, no. 16, pp. 5430-5434, 1983.
16. Holguin MH, Frederick LR, Bernshaw NJ, Wilcox LA, Parker CJ., “Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of erythrocytes of paroxysmal nocturnal hemoglobinuria.,” J Clin Invest, no. 84, pp. 7-17, 1989.
17. Holguin MH, Wilcox LA, Bernshaw NJ, Rosse WF, Parker CJ., “Relationship between the membrane inhibitor of reactive lysis and erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria,” J Clin Invest, no. 84, pp. 1387-1394, 1989.
18. Gargiulo L, Papaioannou M, Sica M., “Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria.,” Blood, vol. 21, no. 14, pp. 2753-2761, 2013.
19. Lee SC, Abdel-Wahab O, “The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance.,” Journal of Clinical Investigation, vol. 124, no. 10, pp. 4227-4230, 2014.
20. Ham TH., “Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria. A study of the mechanism of hemolysis in relation to acid-base equilibrium.,” N Engl J Med, vol. 217, pp. 915-917, 1938.
21. Borowitz MJ, Craig FE, DiGiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, Wittwer CT, Richards SJ, “Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry,” Cytometry B Clin Cytom. , vol. 78, pp. 211-230, 2010.
22. Araten DJ, Nafa K, Pakdeesuwan K, Luzzatto L., “Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.,” Proc Natl Acad Sci USA, vol. 96, pp. 5209-5214, 1999.
23. Hillmen P, Young NS, Schubert J, et al, “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.,” N Engl J Med, vol. 355, no. 12, pp. 1233-1243, 2006.
24. Kelly RJ, Arnold L, Richards S, et al, “The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab,” Brit J Hamatol, vol. 149, pp. 446-450, 2010.
25. Kelly RJ, Hill A, Arnold LM, et al, “Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival.,” Blood, vol. 117, no. 25, pp. 6786-6792, 2011.
26. Young NS, Meyers G, Schrezenmeier H, Hillmen P, Hill A, “The management of paroxysmal nocturnal hemoglobinuria: recent advances in diagnosis and treatment and new hope for patients,” Semin Hematol, vol. 46, pp. S1-S16, 2009.
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NORD is grateful to the following medical expert for serving as an author of this guide: Carlos M. De Castro, III, MD |
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NORD is grateful to the following medical expert for serving as an author of this guide: Wendell Rosse, MD |
This NORD Physician Guide was made possible by an educational grant from Alexion Pharmaceuticals, Inc.
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