Paroxysmal Nocturnal Hemoglobinuria

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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).


View Image

This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, showing the episodic nature of the dark urine (hemoglobin....

The term "nocturnal" refers to the belief that hemolysis is triggered by acidosis during sleep and activates complement to hemolyze an unprotected and abnormal RBC membrane. However, this observation was later disproved. Hemolysis has been 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 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, see eMedicineHealth'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 CD55[8] ; 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.


View Image

This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, showing the episodic nature of the dark urine (hemoglobin....

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 may be due 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 paroxysmal nocturnal hemoglobinuria (PNH) in 5% of cases.[7, 10] The nature of the pathogenetic link between these 2 diseases is still unknown.

Epidemiology

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.

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. The tendency of patients with PNH to suffer thrombosis has been recognized as a major part of the syndrome and interpreted as a very bad prognostic sign and the most common cause of death in PNH. About 30-40% of patients of European origin have serious thrombosis at some time; for unexplained reasons, only 5-10% of patients of East Asian (Chinese, Japanese, and Thai) or Mexican origin develop this complication.[14, 15]

The reason for this propensity is not entirely clear. Intravascular hemolysis may provide altered membrane surfaces upon which coagulation may be initiated. More likely, it is the effect of the activation of complement on platelets and perhaps endothelial cells. In platelets, the deposition of C9 complexes on the surface stimulates their removal by vesiculation; these vesicles are very thrombogenic. Because PNH platelets lack the mechanism for down-regulating C9 deposition (ie, CD59), even a minimal stimulus from activated complement results in a greatly increased production of these vesicles.[16]

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 pseudotumorcerebri.

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 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:

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 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 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.

Pathogenesis

The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin (Hb) are discussed.

RBCs release free Hb into the plasma, which is rapidly dimerized and bound by serum protein haptoglobin and rapidly removed by macrophages, which then degrades it after endocytosis. Since haptoglobin is not recycled, large amounts of free Hb can deplete the body supply, leaving the excess Hb free in the plasma.

When the capacity to manage and degrade free Hb during acute or chronic hemolysis is reached, levels of Hb and heme increase in the plasma and urine. Plasma Hb has the ability to scavenge nitric oxide (NO), resulting in rapid consumption of NO and clinical sequelae of NO depletion.

NO plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma Hb levels during intravascular hemolysis or the administration of Hb preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, PNH, are readily explained by Hb-mediated NO scavenging.

Paroxysms or episodes of symptoms occur during sudden and marked increases in the rate of intravascular hemolysis, and these episodes can be precipitated by infections, drugs, or trauma, or they can occur spontaneously. During paroxysms, PNH patients exhibit symptoms consistent with smooth muscle perturbation through the release of Hb and NO scavenging, including abdominal pain, esophageal spasms, and erectile dysfunction.

Thrombosis is the most common cause of death in 50% of PNH patients and is attributed to venous thrombosis. The most frequent types of thrombosis in this study included hepatic, pulmonary, deep, cerebral, and superficial veins, as well as the inferior vena cava. Interestingly, there is a close correlation between thrombosis and a large PNH clone, and clone size correlates with hemolytic rates.

NO plays an important role in the maintenance of normal platelet functions through the down-regulation of platelet aggregation and adhesion and the regulation of molecules in the coagulation cascade. Accordingly, the long-term consumption of NO by plasma Hb has been implicated in the formation of clots in PNH patients.[17]

Laboratory Studies

Imaging Studies

Other Tests

PIG-A gene mutation analysis is still limited to research laboratories and, although very specific, is still not diagnostic for paroxysmal nocturnal hemoglobinuria (PNH).

Medical Care

Based on current understanding of paroxysmal nocturnal hemoglobinuria (PNH), ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases of PNH with aplastic anemia or those whose conditions transform to leukemia, both of which are life-threatening complications. PNH is a rare, chronic, debilitating, acquired disorder that most frequently presents in early adulthood and usually continuous throughout the life of the patient. PNH results in the death of approximately 50% of affected individuals due to thrombotic complications and, until recently, had no specific therapy.

In 2007, eculizumab, an anti-complement antibody targeting the CD5 complement component, was approved by the US Federal Drug Administration (FDA). This form of therapy alleviates the hemolysis associated with PNH and its sequelae, dramatically improving symptoms, improving quality of life, and eliminating complications of PNH[8] ; however, treatment with eculizumab does not alter the underlying defect of the disease, indicating the need to continue life-long therapy or until spontaneous remission, which occurs only in a minority of patients (12 of 80 patients in a study[11] ) before the advent of eculizumab.

In an international multi-institutional cooperative study, risk of thromboembolic (TE) complications (leading cause of death in PNH) was studied before and after eculizumab therapy in 195 PNH patients. The TE event rate with eculizumab treatment was 1.07, compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment, a relative absolute reduction of 85%. With equalization of duration of exposure before and during treatment for each patient, TE events were reduced from 39 before eculizumab to 3 during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). Eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH and is recommended for PNH patients with a history of prior TE.[23]

The 5-year survival of patients with PNH prior to eculizumab therapy in a cohort followed at Leeds Hospital in the United Kingdom was 66.8%, and the 5-year long-term follow-up after eculizumab has improved to 95.5%, which is not statistically different from an age-matched control from general population.[24] The rate of thrombotic complications prior to eculizumab was 5.6 per 100 patient years; after eculizumab, it dropped to 0.8 per 100 patient years.

Chronic hemosiderosis and/or microvascular thrombosis from PNH causes kidney dysfunction at an incidence of 65% for renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients. Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < .001) compared with baseline and placebo (P = .04). Improvement in renal function was more commonly seen in those with less severe impairment and Improvements occurred quickly and were sustained for at least 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement.[25]

The recommendation on prevention of meningococcal infections due to terminal complement blockade with eculizumab was tetravalent vaccine prior to starting eculizumab; the new recommendation has additional prophylactic antibiotics due to lack of protection for serotype B in the tetravalent vaccine, which happens to be most prevalent in the United Kingdom. They give PenV500 twice daily orally or erythromycin 500 mg twice daily if intolerant to penicillin. The treatment of PNH is largely based on symptoms.

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 with the use of the transferrin saturation index (TSI): Give oral ferrous sulfate if the result is < 20%. (Ferritin is an acute-phase reactant and can be misleading.) Determine steady state hemoglobin levels after correction for iron deficiency. Transfuse packed RBCs (WBCs depleted by filter) when appropriate. Washing RBCs is no longer necessary, and irradiated blood products is recommended for future stem cell transplantation.

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.

The new anticomplement agent eculizumab is a humanized monoclonal antibody against terminal protein C5; it has been shown to be highly effective in reducing intravascular hemolysis.[26, 27] Eleven transfusion-dependent patients with PNH were given intravenous (IV) eculizumab at 900 mg 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 in addition to a global improvement of quality of life.[27] Long-term analysis show that these improvements can be maintained over 3 years, and erythropoietin can overcome anemia due to bone marrow failure in patients on the drug.

Consequences of complement inhibition are of concern for an increased risk of infections from Neisseria meningitides as seen in inherited terminal complement deficiency.[8] Before the administration of eculizumab, all patients should be vaccinated with the tetravalent vaccine (meningococcal ACWY vaccine), if available, as this vaccine covers all except the B strain, for which there is no vaccine available. However, a small risk of 0.5 cases per 100-patient years of septicemia (no meningitis) of meningococcal infections in vaccinated patients can still occur, thus prophylactic antibiotics to avoid this are now recommended.[28]

Treatment breakthrough from complement control can occur in small minority (10%) of patients due to an inadequate dosing schedule. Eculizumab must remain above 35 μg/mL, but trough levels at 2 weeks may fall below this level and cause recurrence of hemolysis.

The recommended adjustment for patients whose eculizumab levels fall into this category is to increase the dose to 900 mg every 12 days or 1200 mg every 2 weeks. Withdrawal hemolysis can occur by stopping therapy for any reason, as accumulation of PNH RBC increases over time by protecting type II and III PNH cells from destruction due to therapy, which can potentially trigger a massive hemolysis.

Monitoring iron even if the patients no longer require transfusions is recommended, because hemosiderinuria no longer occurs with eculizumab, which is a protective mechanism in PNH to excrete iron. Measuring serum ferritin is recommended and chelation therapy may be necessary in patients with high levels.

The risk of meningococcal infection is always present, and although the current vaccinations are protective, it is important to maintain up-to-date vaccinations, which is required every few years according to manufacturer guidelines. Due to the rarity of PNH, the drug is categorized as an ultra-orphan drug and is quite expensive, thus choosing PNH patients who will benefit is important and may not apply to those with hypoplastic anemia or mild asymptomatic hemolysis.

Replacement of nutritional iron, because of increased loss of iron from the hemolysis and the 200-fold 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 process can be prevented by adding prednisone during replacement therapy.

Stimulation of erythropoiesis using androgenic hormones has been successful in patients with a moderate decrease in RBC 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, including using heparin emergently, then maintenance therapy with the use of an oral anticoagulant, such as Coumadin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented using inhibitors of the 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 with paroxysmal nocturnal hemoglobinuria (PNH).

It has been shown that eculizumab therapy, which is effective in decreasing hemolysis, can also decrease the risk for venous thrombosis. Continuation of anticoagulation in patients with PNH with a previous thrombosis while on eculizumab is recommended, as stopping therapy has not been studied. Recent updates[28, 29] show 66% of transfusion-dependent patients became independent, decreasing transfusion requirement of 19.3 units before therapy to 5 units annually. Similarly, a 27% incidence of thrombosis in this population (5.6 events per 100 patient-years) was decreased to 2 thromboses on eculizumab (0.8 events per 100 patient-years; P < .001). Furthermore, 21 patients with no previous thrombosis discontinued warfarin on eculizumab, with no thrombotic sequelae.

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.

Hematopoietic stem cell transplantation (HSCT) using allogeneic donors is the only curative therapy for PNH. With the advent of eculizumab, the indications for HSCT have changed. Clinical results from HSCT from various programs in a rare disease are limited to small numbers of patients. A retrospective analysis of the Italian BM transplantation group in 26 patients with a median age of 32 years (22-60 y, range) with 23 HLA-identical donors (22 sibs, 1 unrelated) shows a transplant-related mortality of 42%, 8% graft failure, and a 10-year survival (disease-free) of 57% for all patients.[30] The mortality rate remains high, so this form of therapy is reserved for those who are severely hypoplastic and refractory to other forms of therapy.

The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in 48 recipients of HLA-identical sibling transplants between 1978 and 1995.[31] Data using nonmyeloablative conditioning and haploidentical donors was similar to the identical donors, indicating some form of graft-versus-PNH effects. Now that an effective, nontransplant therapy is available, the use of allogeneic HSCT to treat PNH has decreased.

Before the introduction of eculizumab, PNH patients with severe symptoms from classic PNH and patients with AA/PNH with peripheral cytopenias meeting criteria for severe aplastic anemia were considered good candidates for allogeneic bone marrow transplantation, especially if a matched sibling donor was available.

With eculizumab for PNH, the indications for allogeneic HSCT in this setting have changed. First, HSCT should not be offered as initial therapy for most patients with classic PNH, given the high transplant-related mortality, especially when using unrelated or mismatched donors. Exceptions are PNH patients in countries where eculizumab is not available. HSCT is also a reasonable option for patients who do not have a good response to eculizumab therapy. Second, AA/PNH patients continue to be reasonable candidates for HSCT if they have life-threatening cytopenias.[32]

Risks of pregnancy in patients with paroxysmal nocturnal hemoglobinuria (PNH) are very significant. There is a very high risk of thrombotic complications for the expectant mother, as well a risk of developing hypoplastic anemia. Maternal mortality in these patients is approximately 20%, mostly from thrombosis and infections, and there is an increased risk of fetal loss. It is recommended that pregnant women with paroxysmal nocturnal hemoglobinuria (PNH) should be fully anticoagulated with low-molecular weight heparin (LMWH). Warfarin may be substituted after the first trimester.

The use of eculizumab in pregnancy has been studied and recently reported.[33] The report shows that eculizumab given from conception to delivery was safe, with no blockade of complement in the cord blood during delivery. Eculizumab does not appear to cross the placenta or be excreted in breast milk, and it reduces the complications of PNH frequently seen in pregnancy.

Consultations

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

Medication Summary

The drugs used in treatment of paroxysmal nocturnal hemoglobinuria (PNH) include eculizumab to stop hemolysis, recombinant erythropoietin or androgens to stimulate erythropoiesis, anticoagulants to treat thrombotic complications, and stimulation of hematopoiesis in the aplastic phase by immunosuppressive agents.

Oxymetholone (Anadrol-50)

Clinical Context:  Anabolic and androgenic derivative of testosterone in an oral formulation.

Used to stimulate erythropoiesis by increasing endogenous levels of erythropoietin and by enhancing the response of precursor cells to the growth factor.

Stanozolol (Winstrol)

Clinical Context:  Anabolic and androgenic derivative of testosterone in an oral formulation.

Danazol (Danocrine)

Clinical Context:  Synthetic steroid analogue, derived from ethisterone, with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action without adverse virilizing and masculinizing effects. Increases levels of C4 component of the complement. May push the resting hematopoietic stem cells into cycle, making them more responsive to differentiation by hematopoietic growth factors. May also stimulate endogenous secretion of erythropoietin.

May impair clearance of immunoglobulin-coated platelets and decreases autoantibody production.

Class Summary

Androgens 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.

Antithymocyte globulin; rabbit (Atgam)

Clinical Context:  Purified preparation of pasteurized polyclonal IgG obtained from rabbits immunized against human thymocytes (T cells) for IV use. This preparation has replaced the Upjohn preparation Atgam (horse serum) and is considered an equivalent.

Class Summary

Antithymocyte globulin is an antiserum to human T cells prepared from horses or rabbits.[34] The mechanism of action of polyclonal antilymphocyte preparations to suppress immune responses is not fully understood.

Eculizumab (Soliris)

Clinical Context:  Orphan drug indicated for treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Blocks complement-mediated destruction of PNH red blood cells. Inhibits C-5 component of complement system, thereby preventing final stages of complement activation.

Class Summary

The C-5 inhibitor eculizumab has been designated as an orphan drug for the treatment paroxysmal nocturnal hemoglobinuria (PNH).

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Complications

Prognosis

Author

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: No financial interests None None

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

References

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  2. Luzzatto L. Paroxysmal nocturnal hemoglobinuria. Hematology 2000. American Society of Hematology Education Program. 2000;28-38.
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This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, 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.

This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, 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.

The Ham test (acidified serum lysis) establishes the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), demonstrating a characteristic abnormality of PNH red blood cells by acidified fresh normal serum. Here is a PNH patient's (Pt) red blood cells lysed by normal serum at room temperature (RT) and at 37°C compared with normal red cells (no hemolysis) (control [C]). 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.

This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, 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.

The Ham test (acidified serum lysis) establishes the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), demonstrating a characteristic abnormality of PNH red blood cells by acidified fresh normal serum. Here is a PNH patient's (Pt) red blood cells lysed by normal serum at room temperature (RT) and at 37°C compared with normal red cells (no hemolysis) (control [C]). 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.