AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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

United States

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.

International

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 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. 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.

CLINICAL

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History

A working classification has been developed 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 BM disorder (eg, PNH/aplastic anemia or PNH/refractory anemia-MDS); and (3) subclinical PNH (PNH-sc) in aplastic anemia are now recognized.

PNH presents in any of the 3 syndromes or sets of symptoms.

• Hemolytic anemia usually is 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 nearly always is present in the urine sediment and can accumulate in the kidneys, which shows up on MRI or 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. Bone marrow usually is markedly erythroid, with decreased or absent iron stores, depending on how long the patient has been losing iron in 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, and 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 include esophageal spasms that occur in the morning and, like the urine, clear up later in the day. In males, impotence can occur concomitant with hemoglobinuria, the cause of which is unknown.

Physical

Most commonly, pallor suggests anemia, fever suggests infections, and bleeding, such as mucosal bleeding, suggests skin ecchymoses in thrombocytopenia similar to aplastic anemia.

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

Causes

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 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 PNH, the peripheral blood and bone marrow is a mosaic composed of GPI-AP+ and GPI-AP- cells; with the 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 pathological 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 BM injury.

DIFFERENTIALS

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Other Problems to be Considered

Thrombocytopenia

WORKUP

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Lab Studies

• The tests involved in establishing the diagnosis demonstrate the presence of RBCs that are exceptionally sensitive to the hemolytic action of complement. The state-of-the-art laboratory test is to send the patient's blood for flow cytometry to detect CD59 (MIRL), a glycoprotein, and CD55 (DAF) in regulation of complement action. Absence or reduced expression of both CD59 and CD55 on PNH red cells is diagnostic.
  
  
  • The use of flow cytometry in PNH differs from many applications in that diagnosis depends upon demonstrating the absence of relevant antigens. In this context, it is important that at least 2 GPI-linked antigens are studied to exclude rare congenital deficiencies of single antigens (CD55 and CD59) and polymorphism with individual antigen (CD16), which renders them undetectable by some monoclonal antibody clones.
  • A more accurate alternative reagent for PNH screening and measuring PNH clone is the bacterial toxin aerolysin (fluorescent aerolysin or FLAER), which binds to RBC via GPI anchor and initiates hemolysis. A modified, nonhemolytic form of a fluorescently labeled molecule has been developed that can detect PNH cells to a level of 0.5%. The advantage of this assay is that it can detect the clone in all hematopoietic cell lineage in one assay.
  • Peripheral blood is the most suitable specimen for immunophenotyping for PNH, and it is important to screen both RBC and granulocytes since red cell transfusions are common among these patients and granulocytes may not be present in severe hypoplastic anemia patients.
  • The value of flow cytometry and monitoring serial analysis for predicting both disease course and clinical phenotype may be important, especially in assessing patients for the likelihood of thrombotic events. Recent studies show that the size of the PNH clone correlates with the risk for venous thrombosis. Patients with less than 50% PNH granulocytes seldom develop thrombosis, while patients with larger clone size appear to be at great risk and will require anticoagulation.
• If performed properly, acidified serum lysis and Ham test (from Thomas Hale Ham) are reliable ways to diagnose PNH (see Image 2). Dr Ham demonstrated that the RBCs in PNH were lysed by complement when normal serum was acidified or activated by alloantibodies.
• • The serum pH is lowered to about 6.2 and the Mg⁺⁺ level is adjusted to 0.005 mol/L to achieve maximum sensitivity. The cells that are hemolyzed are the sensitive cells, and those that remain intact are normal cells, indicating 2-3 subpopulations of red cells in the circulation.
  • A false-positive test result is seen in congenital dyserythropoietic anemia, type II (hereditary erythroblastic multinuclearity with positive acidified serum tests [HEMPAS]). These patients have a negative sucrose hemolysis (sugar water test) results. Some normal serum can give a false-negative Ham test result; thus, the sucrose water test is more sensitive but less specific for PNH.
• The complement lysis sensitivity test of Rosse and Dacie is a more precise method. RBCs are sensitized with a potent lytic anti-i antigen and hemolyzed with limiting amounts of normal serum as a source of complement. This demonstrates 3 groups of RBCs in PNH patients including the following:
• • PNH I cells are normal in sensitivity to complement.
  • PNH II cells are moderately more sensitive than normal cells.
  • PNH III cells are markedly sensitive, requiring one fifteenth to one twentieth of complement for an equal degree of lysis. This group is increased in patients with more severe PNH and is associated with a mean life span of 10-15 days.
• The sugar water or sucrose lysis test uses the ionic strength of serum that is reduced by adding an isoosmotic solution of sucrose, which then activates the classic pathway, and complement-sensitive cells are lysed. This test is less specific but more sensitive than the Ham test, since some RBCs hemolyze from autoimmune hemolytic anemias, leukemia, and aplastic anemia to a minor degree.
• Other tests to demonstrate intravascular hemolysis include the following:
• • Elevated serum LDH
  • Elevated reticulocyte count
  • Low-to-absent serum haptoglobin
  • Hemoglobinuria and hemosiderinuria: The presence of hemolysis may be intermittent and can be missed easily, depending on when the tests are performed.
• Evaluation of hematopoiesis should include a complete blood count (CBC) and a bone marrow examination. This will differentiate an erythroid and hyperplastic marrow during the hemolytic phase or a hypoplastic marrow in the aplastic phase.
• PNH leucocytes have a low leucocyte alkaline phosphatase score, which is similar to that for chronic myelogenous leukemia.
• PNH red cells and other blood cells, because of the missing GPI anchor, are missing membrane proteins DAF (CD55) and MIRL (CD59). This can be detected by flow cytometry as a diagnostic test, which may replace the Ham and sugar water tests.

Imaging Studies

• Thromboses of major veins are best evaluated by radiographic means.
• Investigate hepatic vein thrombosis with a routine technetium Tc 99m colloid scan of the liver and spleen. This often reveals diminished function in all portions of the liver except the caudate lobe, which is spared because it is drained by the inferior vena cava rather than the hepatic vein. An MRI or ultrasound can demonstrate the cessation of flow through the hepatic vein or by injecting or using a dye to demonstrate thrombus in the vein.
• MRI with contrast may demonstrate sagittal vein thrombosis.

TREATMENT

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Medical Care

Based on current understanding of the disease, ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic, because this requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases with aplastic anemia or those whose conditions transform to leukemia, both of which are life-threatening complications. The treatment is largely based on symptoms.

Treatment for anemia, depending on the major cause and severity, can be approached with the following guidelines:

• The anemia may have 3 components: intravascular hemolysis, inadequate erythropoiesis, and superimposed iron deficiency (massive iron loss through hemoglobinuria).
• • In view of increased rate of erythropoiesis, give 5 mg/d of folic acid orally.
  • Assess iron stores using transferrin saturation index (TSI): Give oral ferrous sulfate if <20%. (Ferritin is acute-phase reactant and can be misleading.)
  • Determine steady state Hb levels after correction for iron deficiency.
  • Transfuse packed RBC (WBC depleted by filter) when appropriate. Washing red cells is no longer necessary, and irradiated blood products is recommended for future SCT.
• Modulation of complement is controlled poorly by high doses of glucocorticoids. The usual adult dose of prednisone is 20-40 mg/d (0.3-0.6 mg/kg/d) given daily during hemolysis and changed to alternate days during remission. On this regimen, about 70% of adult patients experience improvement in hemoglobin levels, but long-term therapy is fraught with complications.
• A new anticomplement agent, eculizumab, is a humanized monoclonal antibody against terminal protein C5; it has recently been shown to be highly effective in reducing intravascular hemolysis. Eleven transfusion-dependent PNH patients were given eculizumab at 900 mg IV over 30 minutes every 2 weeks. The mean LDH decreased along with transfusion requirements from 2.1 units per patient per month to 0.0 along with global improvement of quality of life. Long-term analysis show that these improvements can be maintained over 3 years now, and erythropoietin can overcome anemia due to marrow failure in patients on the drug. The current studies are closed for recruitment, and the data will be submitted for licensing. In March, 2007, the FDA approved eculizumab as an orphan drug for PNH.
• Replacement of nutritional iron, because of increased loss of iron from the hemolysis and the 200 times increase in iron urinary excretion, is necessary to prevent development of iron deficiency. Iron replacement can stimulate reticulocytosis that can trigger hemolysis by releasing a new cohort of complement-sensitive cells. This can be prevented by adding prednisone during replacement therapy.
• Stimulation of erythropoiesis using androgenic hormones has been successful in patients with moderate decrease in red cell production. This has been replaced mainly by using recombinant erythropoietin therapy.
• Supportive care for severe anemia includes blood transfusion using leuko-depleted packed RBCs to prevent alloimmunization. Development of alloantibodies can be a problem with future transfusions because of activation of complement and delayed hemolysis of transfused blood.
• Management of thrombotic complications follows standard principles, using heparin emergently, then maintenance using an oral anticoagulant, such as Coumadin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented using inhibitors of cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone. Primary prophylaxis with warfarin has been advocated, but it remains controversial as to whether this approach is safe and effective in all patients PNH. It remains to be seen if eculizumab therapy, which is effective in decreasing hemolysis, can also decrease the risk for venous thrombosis.
• Bone marrow hypoplasia is a serious cause of morbidity and mortality. It is treated most effectively with bone marrow transplantation; however, if there is no suitable donor available, antithymocyte globulin (ATG) has been used in the treatment of aplastic anemia with considerable success.

Consultations

In centers that do not have a bone marrow transplantation program, consultation and identification of possible donors should be undertaken early.

• Stem cell transplantation (SCT) is a curative therapeutic option for PNH. However, the risks must be carefully weighed against factors related both to PNH and comorbid conditions. Furthermore, the heterogenous presentation of the disease, its unpredictable course, and its association with bone marrow failure conditions confound the decision process regarding transplantation.
• A recent analysis by the International PNH Interest Group reviewed data from 67 patients from single centers and from 2 registry studies with special emphasis in eliminating duplication in patient reporting.
• • Among the 67 patients, 7 were transplanted from a twin syngeneic donor. Four of the 7 syngeneic transplants had no conditioning therapy, and these 4 either failed to engraft or relapsed posttransplant indicating that a marrow ablative conditioning is necessary before syngeneic transplantation.
  • In 47 of 67 patients, an HLA-identical sibling was used as the donor, 1 from a haploidentical family member, and 12 from an unrelated donor (MUD).
  • In the only single-center study providing a Kaplan-Meier analysis, overall survival at 5 years was 58 +/- 13%. This is less favorable than the survival estimate of approximately 75% generated by combining the data from the other reports.
  • Investigation on whether reduced intensity conditioning can improve the outcome is currently underway.

MEDICATION

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The drugs used in treatment of PNH include androgens to stimulate erythropoiesis, anticoagulants to treat thrombotic complications, and stimulation of hematopoiesis in aplastic phase by immunosuppressive agents.

Drug Category: Androgens

These agents are used to stimulate erythropoiesis by increasing endogenous levels of erythropoietin and by enhancing the response of precursor cells to the growth factor.

Attenuated androgens, such as danazol, are recommended for use in women, as the attenuated androgen has fewer adverse virilizing and masculinizing effects.

Drug Category: Immunosuppressive agents

Antithymocyte globulin is an antiserum to human T cells prepared from horses or rabbits. Mechanism of action of polyclonal antilymphocyte preparations to suppress immune responses is not fully understood.

Drug Category: Complement Inhibitor

The C-5 inhibitor, eculizumab, has been recently designated as an orphan drug for PNH.

FOLLOW-UP

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Further Inpatient Care

• In severe cases with an aplastic phase, referral to a bone marrow transplantation center is indicated for possible allogeneic bone marrow transplant (BMT). Umbilical cord stem cell transplantation from the patient's own cord blood, from a related donor, or from the registry for human leukocyte antigen–matched unrelated donors may be an option in pediatric patients.

Further Outpatient Care

• In many patients, the abnormal clone eventually may disappear. This usually takes at least 5 years and often as long as 15-20 years. Reactivation of PNH in these patients has been observed with acute infections. Patients with chronic anemia alone, without thrombotic complications, can live relatively normal lives for many years.

In/Out Patient Meds

• Outpatient RBC transfusion often is necessary to keep a patient with chronic anemia PNH able to function and live a normal life.

Complications

• Primary physicians should be aware of the thrombotic complications and how to diagnose them when they occur.

Prognosis

• Prognosis is variable, depending on the severity of symptoms and presence of complications. An aplastic phase is a serious prognostic factor, because the resulting pancytopenia and thrombosis of hepatic, abdominal, and cerebral veins can lead to life-threatening consequences. Prophylactic anticoagulation has not been shown to be of benefit because of a lack of data in a clinical trial setting.

MISCELLANEOUS

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Special Concerns

• The disease mimics other conditions and sometimes may be difficult to diagnose unless it is included in the differential diagnosis. In cases with unusual large-vein thrombosis, such as Budd-Chiari syndrome or pancytopenia with hypoplastic bone marrow, patients should be screened for PNH using a Ham test, a sugar water test, and, now, a peripheral blood flow cytometry for CD59.

MULTIMEDIA

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Media file 1:  This series of containers holds urine of a patient with PNH, showing the episodic nature of the dark urine (hemoglobinuria) during intravascular hemolysis, usually occurring at night. Early morning urine is cola-colored. This may occur at different times of the day and vary from patient to patient. Permission to use this image has been granted by the American Society of Hematology Slide Bank; 3rd Edition.
	View Full Size Image
Media type:  Photo

Media file 2:  The Ham test (acidified serum lysis) establishes the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) demonstrating a characteristic abnormality of PNH red cells by acidified fresh normal serum. Here is a PNH patient's red cells lysed by normal serum at room temperature (RT) and at 37°C compared to normal red cells (no hemolysis). Heated serum at 56°C inactivates complement and prevents hemolysis in PNH cells. Permission to use this image has been granted by the American Society of Hematology Slide Bank; 3rd Edition.
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Media type:  Photo

REFERENCES

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• Araten DJ, Thaler HT, Luzzatto L. High incidence of thrombosis in African-American and Latin-American patients with Paroxysmal Nocturnal Haemoglobinuria. Thromb Haemost. Jan 2005;93(1):88-91. [Medline].
• Bessler M, Hillmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal hemoglobinuria. Semin Hematol. Apr 1998;35(2):149-67. [Medline].
• Brodsky RA, Mukhina GL, Li S. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. Sep 2000;114(3):459-66. [Medline].
• Ebenbichler CF, Wurzner R, Sandhofer AD, et al. Anti-thymocyte globulin treatment of a patient for paroxysmal nocturnal haemoglobinuria-aplastic anaemia syndrome: complement activation and transient decrease of the PNH clone. Immunobiology. 1996-97;196(5):513-21. [Medline].
• Graham ML, Rosse WF, Halperin EC, et al. Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol. Mar 1996;92(3):707-10. [Medline].
• Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. Nov 15 2003;102(10):3587-91. [Medline].
• Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. Oct 1 2005;106(7):2559-65. [Medline].
• Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. Feb 5 2004;350(6):552-9. [Medline].
• Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. Nov 9 1995;333(19):1253-8. [Medline].
• Luzzatto L. Paroxysmal nocturnal hemoglobinuria. In: Hematology 2000. American Society of Hematology Education Program;2000:28-38. [Full Text].
• Nagarajan S, Brodsky RA, Young NS, Medof ME. Genetic defects underlying paroxysmal nocturnal hemoglobinuria that arises out of aplastic anemia. Blood. Dec 15 1995;86(12):4656-61. [Medline].
• Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). May 2004;83(3):193-207. [Medline].
• Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. Dec 1 2005;106(12):3699-709. [Medline].
• Rosse WF. Paroxysmal nocturnal hemoglobinuria. In: Blood: Principles and Practice of Hematology. Baltimore, Md: Lippincott Williams & Wilkins; 1995:367-376.
• Rosse WF, Ware RE. The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood. Nov 1 1995;86(9):3277-86. [Medline].
• Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. Aug 31 1996;348(9027):573-7. [Medline].
• Young NS. Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia. Semin Hematol. Jan 2000;37(1):3-14. [Medline].

Article Last Updated: Sep 20, 2007