Paroxysmal Nocturnal Hemoglobinuria

Last Updated: May 26, 2006

Author: Emmanuel C Besa, MD, Professor of Medicine, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland

Emmanuel C Besa, MD, is a member of the following medical societies: American Association for Cancer Education, American Association for the Advancement of Science, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Editor(s): Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Marcel E Conrad, MD, Distinguished Professor of Medicine, University of South Alabama; Director Cancer Center, Clinical Cancer Research Program, The Cancer Center, Mobile Infirmary Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; and Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice

INTRODUCTION

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a descriptive term for the clinical manifestation of red cell breakdown with release of hemoglobin into the urine that is manifested most prominently by dark-colored urine in the morning. The term "nocturnal" refers to the belief that hemolysis is triggered by acidosis during sleep and activates complement to hemolyze an unprotected and abnormal red cell membrane. However, this observation later was disproved. Hemolysis is shown to occur throughout the day and is not actually paroxysmal, but the urine concentrated overnight produces the dramatic change in color.


This disease has been referred to as the great impersonator because of the variety of symptoms observed during the initial manifestation and course of the disease. The clinical syndrome can present in 3 types of symptoms including (1) an acquired intracorpuscular hemolytic anemia due to the abnormal susceptibility of the red cell membrane to the hemolytic activity of complement; (2) thromboses in large vessels, such as hepatic, abdominal, cerebral, and subdermal veins; and (3) a deficiency in hematopoiesis that may be mild or severe, such as pancytopenia in aplastic anemia state. The triad of hemolytic anemia, pancytopenia, and thrombosis makes PNH a truly unique clinical syndrome.


Pathophysiology: PNH currently is reclassified from purely an acquired hemolytic anemia due to a hematopoietic stem cell mutation defect. This change in concept was brought about by the observation that surface proteins were missing not only in the red cell membrane but also in all blood cells, including the platelet and white cells.

The common denominator in the disease, a biochemical defect, appears to be a genetic mutation leading to the inability to synthesize the glycosyl-phosphatidylinositol (GPI) anchor that binds these proteins to cell membranes. The corresponding gene PIGA (phosphatidylinositol glycan class A) in the X chromosome can have several mutations, from deletions to point mutations. The essential group of membrane proteins that are lacking in all hematopoietic cells are called complement-regulating surface proteins, including the decay-accelerating factor (DAF) or CD55, homologous restriction factor (HRF) or C8 binding protein, and membrane inhibitor of reactive lysis (MIRL) or CD59. All of these proteins interact with complement proteins, particularly C3b and C4b, dissociate the convertase complexes of the classic and alternative pathways, and halt the amplification of the activation process. Hemolytic anemia is due to intravascular destruction of red blood cells (RBCs) by complement with varying degrees.

The classic description of the manifestations of PNH is the presence of dark urine during the night with partial clearing during the day (see Image 1); however, hemoglobinuria may occur every day in severe cases, more frequently in episodes lasting 3-10 days, or, in some cases, not at all. Thrombosis of the veins usually manifests as a sudden catastrophic complication, with severe abdominal pain and rapidly enlarging liver and ascites (Budd-Chiari syndrome). This thrombosis is secondary to a lack of CD59 on platelet membranes that induces platelet aggregation and is highly thrombogenic, particularly in the venous system. Deficient hematopoiesis may occur due to diminished blood cell production with a hypoplastic bone marrow; thus, patients have a 10-20% chance of developing aplastic anemia in their course, and patients known to have aplastic anemia eventually develop PNH in 5% of cases. The nature of the pathogenetic link between these two diseases still is unknown.

Frequency:

• In the US: PNH is an uncommon disorder of unknown frequency both in the United States and worldwide. There is little information on the incidence of PNH, but the rate is estimated to be 5-10 times less than that of aplastic anemia; thus, PNH is a rare disease. Attempts to get a more accurate incidence and to learn more about its natural course is currently under way under the auspices of The Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. This is a comprehensive, observational, multinational effort to document the clinical outcomes in the treatment of patients with PNH.

• Internationally: It has been suggested that, like aplastic anemia, PNH may be more frequent in Southeast Asia and in the Far East.

Mortality/Morbidity: The disease process is insidious and has a chronic course, with a median survival of about 10.3 years. Morbidity depends on the variable expressions of hemolysis, bone marrow failure, and thrombophilia that define the severity and clinical course of the disease. In several large studies, the main cause of death in patients was venous thrombosis, followed by complications of bone marrow failure; however, spontaneous long-term remission or leukemic transformation of the PNH clone has been reported and well documented.

• The median survival after diagnosis was 10 years in a series of 80 consecutive patients seen at the Hammersmith Hospital in London treated with supportive measures, such as oral anticoagulant therapy after an established thromboses, and transfusions. Sixty patients died; 28 of the 48 whose cause of death was known died from venous thrombosis or hemorrhage. Thirty-one patients (39%) had one or more episodes of venous thrombosis during their illness. No leukemic transformations occurred in this series.

• Twenty-two of the 80 patients (28%) survived for 25 years. Of the 35 patients who survived for 10 years or more, 12 had spontaneous clinical recovery at which time no PNH-affected cells were found among the red cells or neutrophils during their prolonged remission, but a few PNH-affected lymphocytes were detectable in 3 of 4 patients tested.

Race: The differences among races were shown comparing 176 American patients seen at Duke University and 209 patients from Japan. White American patients were younger with significantly more classic symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia and a smaller PNH clone. Survival analysis showed a similar death rate in each group, although causes of death were different with more thrombotic deaths seen in American patients. Japanese patients had a longer mean survival time (32.1 vs 19.4 y), but Kaplan-Meier survival curves were not significantly different.

• Other geographic ethnic differences were observed in thrombosis incidence in 64 patients with classic PNH. They found that African Americans (n=11) and Latin Americans (n=8) had a higher risk or rate of thrombosis by Cox regression and had an impact on length of survival compared to others (n=45).

Sex: Men and women are affected equally, and no familial tendencies exist.
Age: PNH may occur at any age from children (10%) as young as 2 years to adults as old as 83 years, but it frequently is found among young adults with a median age at the time of diagnosis was 42 years (range, 16-75 y) from a series in England of 80 consecutive patients. In childhood through adolescence, patients presented with more of the primary features of aplastic anemia than the normal adult population. Other complications, such as infections and thrombosis, occurred with equal frequency in all age groups.

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