eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Paroxysmal Nocturnal Hemoglobinuria

Author: Emmanuel C Besa, MD, Professor, 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
Contributor Information and Disclosures

Updated: Mar 27, 2009

Introduction

Background

Paroxysmal nocturnal hemoglobinuria (PNH) is a descriptive term for the clinical manifestation of red blood cell (RBC) breakdown with release of hemoglobin into the urine that is manifested most prominently by dark-colored urine in the morning (see image below).

This disease has been referred to as the great impersonator because of the variety of symptoms observed during the initial manifestation and course of paroxysmal nocturnal hemoglobinuria (PNH). The clinical syndrome can present in 3 types of symptoms including (1) an acquired intracorpuscular hemolytic anemia due to the abnormal susceptibility of the RBC 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 an aplastic anemia state.^1,2,3,4 The triad of hemolytic anemia, pancytopenia, and thrombosis makes paroxysmal nocturnal hemoglobinuria (PNH) a truly unique clinical syndrome.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

Paroxysmal nocturnal hemoglobinuria (PNH) has been 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 RBC 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.^4,5,6 The corresponding gene PIGA (phosphatidylinositol glycan class A) in the X chromosome can have several mutations, from deletions to point mutations.⁷

Due to its location on the X chromosome, and due to X inactivation in female somatic cells, only one mutation is required in either males or females to abolish the expression of GPI-linked proteins. Most type II paroxysmal nocturnal hemoglobinuria (PNH) cells (total lack of GPI-linked protein) are due to a frame shift mutation occurring in the early hematopoietic progenitor cells, resulting in same mutation in all blood cell lines.

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 CD55⁸ ; homologous restriction factor (HRF), or C8 binding protein; and membrane inhibitor of reactive lysis (MIRL), or CD59.⁹ 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 RBCs by complement, with varying degrees in the absence of these regulating proteins resulting in uncontrolled amplification of the complement system that leads to destruction of the RBC membrane.

Breakdown of RBC membranes by complement leads to the release of hemoglobin into the circulation. Hemoglobin is bound to haptoglobin for efficient clearance from the circulation. After saturating the haptoglobin, free forms of hemoglobin circulates and binds irreversibly with nitric oxide (NO) and depletes NO levels in peripheral blood. Because NO is a smooth muscle tone regulator, depletion of NO levels leads to smooth muscle contraction with consequent vasoconstriction, constriction of the gut, and pulmonary hypertension. Symptoms of abdominal pain, bloating, back pain, headaches, esophageal spasms, erectile dysfunction, and fatigue are due to NO depletion by scavenging free hemoglobin.

Progressive chronic renal failure can occur after several years of hemoglobinuria from the acute tubulonecrosis effects of heme and iron (pigment nephropathy), decreased renal perfusion from renal vein thrombosis, and tubular obstruction with pigment casts. Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience a high incidence (40%) of thrombotic events (mostly venous) in large vessels (cerebral, hepatic, portal, mesenteric, splenic, and renal veins) and, most recently recognized, arterial thrombosis.

The pathophysiology of thrombophilia in paroxysmal nocturnal hemoglobinuria (PNH) is not fully understood, but the increased incidence that occurs during hemolytic episodes suggest a direct relationship with the hemolytic process. Increased procoagulant and fibrinolytic activity, suggesting increased fibrin generation, and turnover, increased plasma levels of urokinase-type plasminogen activator and platelets deficient in GPI-linked proteins activated by complement, have been implicated. However, none of these identified platelet and coagulation abnormalities can fully explain the hypercoagulable state in paroxysmal nocturnal hemoglobinuria (PNH).

Bone marrow failure is present in all patients with paroxysmal nocturnal hemoglobinuria (PNH), even when peripheral blood counts are normal and the bone marrow is hypercellular. The degree of marrow failure may vary from severe aplastic anemia and show evidence of a decreased number of hematopoietic stem cells, possibly due to similar destruction by complement, but the cause(s) are still poorly understood.

The classic description of the manifestations of paroxysmal nocturnal hemoglobinuria (PNH) is the presence of dark urine during the night with partial clearing during the day (see image below); however, hemoglobinuria may occur everyday in severe cases, more frequently in episodes lasting 3-10 days, or, in some cases, not at all.

Frequency

United States

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder of unknown frequency both in the United States and worldwide. There is little information on the incidence of paroxysmal nocturnal hemoglobinuria (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 PNH Patient Registry. This is a comprehensive, observational, multinational effort to document the clinical outcomes in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

International

It has been suggested that, like aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) may be more frequent in Southeast Asia and in the Far East.

Mortality/Morbidity

The disease process of paroxysmal nocturnal hemoglobinuria (PNH) 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 with paroxysmal nocturnal hemoglobinuria (PNH) 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 who were treated with supportive measures, such as oral anticoagulant therapy after an established thrombosis, and transfusions.¹¹ Sixty patients died; of 48 patients whose cause of death was known, 28 died from venous thrombosis or hemorrhage. Thirty-one individuals (39%) had one or more episodes of venous thrombosis during their illness.¹¹ No leukemic transformations occurred in this series.Twenty-two of the 80 patients (28%) survived for 25 years.¹¹ 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 RBCs or neutrophils during their prolonged remission, but a few PNH-affected lymphocytes were detectable in 3 of 4 patients tested.¹¹

Race

The differences of paroxysmal nocturnal hemoglobinuria (PNH) among races were shown in a study that compared 176 American patients seen at Duke University and 209 patients from Japan.¹² White American patients were younger with significantly more classic symptoms of the disease, including thrombosis, hemoglobinuria, and infection, whereas Asian patients were older with more marrow aplasia and a smaller PNH clone. Survival analysis showed a similar death rate in each group, although the causes of death were different, with more thrombotic deaths seen in the 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.¹²

Other geographic ethnic differences were observed in the thrombosis incidence in 64 patients with classic paroxysmal nocturnal hemoglobinuria (PNH).¹³ The investigators found that African Americans (n = 11) and Latin Americans (n = 8) had a higher risk or rate of thrombosis by Cox regression analysis and had an impact on length of survival compared with other patients (n = 45).

Sex

Men and women are affected equally with paroxysmal nocturnal hemoglobinuria (PNH), and no familial tendencies exist.

Age

Paroxysmal nocturnal hemoglobinuria (PNH) may occur at any age, from children (10%) as young as 2 years to adults as old as 83 years, but it is frequently found among adults, with a median age at the time of diagnosis of 42 years (range, 16-75 y) from a series in England of 80 consecutive patients.¹¹ In childhood through adolescence, patients with paroxysmal nocturnal hemoglobinuria (PNH) presented with more of the primary features of aplastic anemia than the healthy adult population. Other complications, such as infections and thrombosis, occurred with equal frequency in all age groups.

Clinical

History

A working classification has been developed for paroxysmal nocturnal hemoglobinuria (PNH) that includes all the variations in the presentation, clinical manifestations, and natural history among PNH patients: (1) classic PNH, (2) PNH in the setting of another specified bone marrow disorder (eg, PNH/aplastic anemia or PNH/refractory anemia-myelodysplastic syndrome [MDS]), and (3) subclinical PNH (PNH-sc) in aplastic anemia are now recognized.

Paroxysmal nocturnal hemoglobinuria (PNH) presents in any of the 3 syndromes or sets of symptoms.

• Hemolytic anemia is usually in the form of intravascular hemolysis.
  • The most common presentation is the presence of anemia associated with dark cola-colored urine that is a manifestation of hemoglobinuria. The latter may be confused with hematuria, and erroneous treatment could be given for urosepsis. Hemosiderin is nearly always present in the urine sediment and can accumulate in the kidneys, which shows up on magnetic resonance images (MRI) or computed tomography (CT) scans.
  • Elevated reticulocyte count and serum lactic acid dehydrogenase (LDH) with a low serum haptoglobin in the absence of hepatosplenomegaly are the hallmarks of intravascular hemolysis. The bone marrow is usually markedly erythroid, with decreased or absent iron stores, depending on how long the patient has been losing iron in the urine.
• Thrombosis involves the venous system, and it usually occurs in unusual veins, namely the hepatic, abdominal, cerebral, and subdermal veins.
  • Hepatic vein thrombosis results in Budd-Chiari syndrome, which manifests as a sudden and catastrophic event characterized by jaundice, abdominal pain, a rapidly enlarging liver, and accumulation of ascitic fluid. This syndrome may be severe and lead to vascular collapse and death, or it can be slow and insidious, leading to hepatic failure.
  • Abdominal vein thrombosis presents with upper abdominal pain, or it can occur anywhere in the abdomen, lasting 1-6 days. It can lead to bowel infarction in severe cases.
  • Cerebral vein thrombosis can range from the mildest form to a severe headache, depending on which veins are involved. The sagittal vein is commonly affected, which can give rise to papilledema and pseudotumor cerebri.
  • Dermal vein thrombosis manifests as raised, painful, red nodules in the skin affecting large areas, such as the entire back, which subsides within a few weeks, usually without necrosis. In cases that do result in necrosis, skin grafting may be necessary.
• Deficient hematopoiesis usually presents with anemia despite the presence of an erythroid marrow with suboptimal reticulocytosis. In some cases, neutropenia and thrombocytopenia can occur in a hypoplastic bone marrow similar to aplastic anemia (aplastic episodes).
• Other symptoms of paroxysmal nocturnal hemoglobinuria (PNH) include esophageal spasms that occur in the morning and, like the dark-colored urine, clear up later in the day. In males, impotence can occur concomitant with hemoglobinuria, the cause of which is unknown.

Physical

Most commonly, in patients with paroxysmal nocturnal hemoglobinuria (PNH), pallor suggests anemia, fever suggests infections, and bleeding, such as mucosal bleeding, suggests skin ecchymoses in thrombocytopenia similar to aplastic anemia. Other physical examination findings may include the following:

• Hepatomegaly and ascites in the presence of Budd-Chiari syndrome
• Splenomegaly if there is splenic vein thrombosis
• Absent bowel sounds in the presence of bowel necrosis
• Papilledema in the presence of cerebral vein thrombosis
• Skin nodules that are red and painful in the presence of dermal vein thrombosis

Causes

Paroxysmal nocturnal hemoglobinuria (PNH) is now known to be a consequence of nonmalignant clonal expansion of one or several hematopoietic stem cells that are deficient in GPI-anchor protein (GPI-AP) acquired through a somatic mutation of PIG-A.

• Recent information has led us to understand that paroxysmal nocturnal hemoglobinuria (PNH) is not a monoclonal disease with a malignant phenotype. Rather, the clinical pathology may actually be an epiphenomenon resulting from an adaptive response to injury, such as an immune attack on the stem cells of hematopoiesis.
• In paroxysmal nocturnal hemoglobinuria (PNH), the peripheral blood and bone marrow is a mosaic composed of GPI-AP+ and GPI-AP- cells; with GPI-AP-, cells can be derived from multiple mutant stem cells. The GPI-AP- mutant cells may appear to dominate hematopoiesis in PNH by providing a proliferative advantage under some pathologic conditions. For example, if damage to stem cells causing bone marrow failure is mediated through a GPI-linked surface molecule, the PNH cells lacking these molecules will survive. The close association with aplastic anemia and MDS suggests that the selection process arises as a consequence of this specific type of bone marrow injury.

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