INTRODUCTION — Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder characterized by a defect in the GPI anchor due to an abnormality in the PIG-A gene. This leads to partial or complete absence of certain GPI-linked proteins, particularly CD59 (also called membrane inhibitor of reactive lysis, protectin, and membrane attack complex inhibitory factor) and CD55 (decay accelerating factor) [1]. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Missing cell proteins").
This topic review will discuss the spectrum of clinical manifestations that can result from these defects. The diagnosis and treatment of this disorder are discussed separately. (See "Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria").
The clinical manifestations of PNH are primarily related to abnormalities in hematopoietic function, including hemolytic anemia, a hypercoagulable state, and bone marrow aplasia. Progression to myelodysplastic syndrome or acute leukemia can also occur. A large retrospective study of 220 patients found that the eight year rates of the major complications of PNH (pancytopenia, thrombosis, and myelodysplastic syndrome) were 15, 28, and 5 percent, respectively [2]. This report also demonstrated the considerable mortality associated with PNH. The median survival was 14.6 years with Kaplan-Meier survival estimates of 78, 65, and 48 percent at 5, 10, and 15 years after diagnosis, respectively.
There has been an ongoing effort to correlate the clinical manifestations of the disorder with the biochemical defects that have been defined. The success of this approach has been variable, depending upon the specific abnormality [1].
HEMOLYTIC ANEMIA — Hemolytic anemia of variable severity is a constant feature of PNH; its paroxysmal nature accounts for the name of this disorder. The hemolysis is mediated by complement activation. The sensitivity of red cells in PNH to the hemolytic action of complement is due to the partial or complete absence of several GPI-linked proteins: CD55 (decay accelerating factor); CD59; and possibly C8 binding protein. The absence of CD59 is clearly the most important.
Different populations of red cells have been defined in PNH according to the status of GPI-linked proteins: PNH III cells — complete absence PNH II cells — partial absence PNH I cells — normal
Determinants of hemolysis — It is the complement-sensitive cells that are destroyed in vivo [3]. PNH III cells are destroyed in a random fashion with a total life span of less than 20 days (normal: approximately 100 days). PNH II cells have an intermediate life span of approximately 45 days that varies with their expression of CD59.
The clinical hemolysis seen in PNH is related to three factors: The proportion of cells that are abnormal. Patients with fewer than 20 percent abnormal cells almost always have evidence of hemolysis and hemosiderinuria but rarely have hemoglobinuria. In contrast, many patients with more than 60 percent PNH III cells have frequent, often daily episodes of hemoglobinuria and crises. However, for reasons that are unclear, some patients do not have such episodes. Hemolysis can be precipitated by the administration of iron to an iron-deficient patient; in this setting, a large number of complement-sensitive cells are delivered to the circulation at one time [4]. The degree of abnormality of the cells. Patients with cells of intermediate abnormality have less hemolysis than patients with an equal number of PNH III cells. Partial restoration of CD55 to completely deficient cells increases their life span in the circulation [5]. The degree to which complement is activated. Hemolysis is most pronounced when complement is activated by viral (particularly gastrointestinal viruses) or bacterial infections. Nocturnal hemolysis in PNH has been attributed to the intestinal absorption of lipopolysaccharide, a potent activator of complement [6].
Renal disease — Intravascular hemolysis in PNH can lead to two forms of renal disease. First, an acute attack, either spontaneous or precipitated by blood transfusion, with massive hemoglobinuria can cause acute renal failure [7,8]. (See "Clinical features and prevention of heme pigment-induced acute tubular necrosis").
Second, chronic hemolysis results in iron deposition in the kidneys in almost all patients. The excess iron can be detected by magnetic resonance imaging [9,10] and, in some cases, by metal detectors at airports. Iron deposition can result in proximal tubular dysfunction [11,12]; in addition, chronic renal failure due to hemosiderosis can occur in patients with long-standing PNH [11,13].
VENOUS THROMBOSIS — PNH is associated with a marked increase in venous thrombosis in the hepatic, other intraabdominal, and peripheral veins. The risk of thrombosis, as well as the risks for hemoglobinuria, abdominal pain, esophageal spasm, and impotence, appear to be significantly related to the size of the PNH clone (see "Esophageal spasm" below and see "Sexual dysfunction" below) [14]. In two series almost all patients developing thrombosis had more than 50 percent [15] or more than 61 percent [14] PNH granulocytes.
This finding may help to explain the different incidences of thrombosis between reports from Asia (<10 percent) [16,17] and the United States and Europe (40 percent) [2,18]. In a comparative study, we found a significantly higher percentage of PNH granulocytes in patients seen at Duke compared to those seen in Japan (69 versus 43 percent) [15].
Once thrombosis has occurred in an organ, it usually tends to recur in the same site. This pattern may reflect residual endothelial proliferation from the initial episode [19]. Asymptomatic patients who have had an episode of venous thrombosis often have evidence of continued activation of coagulation, as manifested by elevated levels of cross-linked fibrinogen and of D-dimer, a product of fibrin breakdown; these changes are not seen in patients without prior venous thrombosis.
Hepatic vein thrombosis — Venous thrombosis most often occurs in the intraabdominal veins, particularly the hepatic veins [20-22]. The onset of hepatic vein thrombosis may be insidious or can occur suddenly, frequently in the setting of a hemolytic episode [21].
Hepatic vein thrombosis was, in the past, detected radiographically by venography. This approach has largely been replaced by MR imaging [9,10]; CT scanning and ultrasonography also have been used [23]. However, even these very sensitive techniques may miss thrombosis of hepatic venous radicals. (See "Clinical manifestations, diagnosis, and treatment of the Budd-Chiari syndrome").
Once it has occurred, hepatic vein thrombosis tends to recur, ultimately causing cirrhosis and rerouting of the blood from the portal drainage. The latter change is exaggerated by thrombosis of the portal vein, which often occurs in the same patient [10]. The development of the Budd-Chiari syndrome is associated with a poor prognosis.
Thrombosis of other intraabdominal veins — Thrombosis of other intraabdominal veins, particularly the portal vein, the splenic vein, and the inferior vena cava, is also common in PNH. This may result in splenomegaly of sufficient severity to produce hypersplenism requiring splenectomy or splenic rupture [24].
Microvascular thrombosis of splanchnic vessels can also occur in PNH. This can produce a number of clinical manifestations including bouts of severe abdominal pain and mucosal ulceration [25]. Surgical removal of the ulcer may lead to resolution of the painful episodes [26].
Large vein thrombosis can be detected by MRI, CT scanning, or ultrasound with Doppler flow measurements. However, identification of thrombosis of smaller vessels is rarely accomplished.
Thrombosis of cerebral veins — Thrombosis of the cerebral veins occurs less frequently in PNH than involvement of the intraabdominal veins. Cerebral vein thrombosis can occur as a catastrophic event or with an insidious onset that may be confused with other causes of headache [27-29]. The major venous sinuses are most often involved, but thrombosis may be limited to the veins covering the cerebrum, particularly the parietal lobe. The diagnosis of cerebral vein thrombosis is often difficult to establish, even with modern imaging techniques.
Thrombosis of other veins — The thrombotic process can affect a variety of other veins including those of the extremities, epididymis (sometimes confused with orchitis), cavernous sinus (causing priapism), kidneys, and skin. Dermal vein thrombosis can present as discrete areas of erythema, swelling, and pain or as a syndrome resembling purpura fulminans [30].
Pathogenesis — Because the hematopoietic cells are abnormal in PNH, it has been assumed that the defects are somehow responsible for the occurrence of thrombosis. Preliminary data suggest that low grade in vivo activation of clotting is common in PNH, an abnormality that is enhanced with increased activation of complement. Increased platelet aggregation, enhanced expression of tissue factor, and impaired fibrinolysis all may contribute to this process.
The platelets in PNH, like the red cells, lack the complement defense proteins CD55 and CD59. Some of the function of CD55 to prevent excess complement activation can be subsumed by the release of factor H from internal granular stores [31]; factor H is a serum factor able to disrupt the C3bBb complex, as CD55 does, and to provide a cofactor for factor I, a serine proteinase that cleaves C3b of the complex [32].
More importantly, normal platelets are able to isolate nascent membrane attack complexes (MACs) in patches that can then be removed by vesiculation [33-35]. The external faces of these vesicles become sites of assembly of the prothrombinase complex because of their ability to bind factor V of the coagulation system [36]. (See "Overview of hemostasis"). In PNH, the formation of MAC complexes occurs at a much greater rate for a given amount of bound C5b-8 because CD59 is not present to prevent the conversion of C9; as a result, many more vesicles are budded from the platelets, resulting in a marked increase in prothrombinase activity [37]. The thrombin that is generated is able to react with the thrombin receptor on the platelet, leading to platelet activation and aggregation and possibly the initiation of clot formation [38].
The localization of the clot to the vessel wall may occur because complement activation and the generation of membrane attack complexes on the defective blood cells stimulate endothelial cells to express tissue factor [39]. Tissue factor provides the site on cells for activation of the so-called "tissue activation pathway" of coagulation. (See "Overview of hemostasis"). Such a site would provide a localizing area for aggregated platelets, particularly in areas where the flow of blood is sufficiently slow to allow stimulation of the endothelium to occur and aggregated platelets to adhere.
Another possible contributing factor to venous thrombosis in PNH is delayed fibrinolysis. Fibrinolysis is promoted by the activation of plasminogen to plasmin, a reaction that is catalyzed by urokinase-like plasminogen activators. This reaction is localized at the cell surface by urokinase plasminogen activator receptor (UPAR) which is present on monocytes but not on platelets. Monocytes are thought to infiltrate thrombi and initiate fibrinolysis. UPAR is GPI-linked and is therefore deficient in PNH monocytes.
DIMINISHED HEMATOPOIESIS — Paroxysmal nocturnal hemoglobinuria is often associated with diminished hematopoiesis, which can lead to cytopenias or aplastic anemia (AA). Patients who present with the clinical manifestations of PNH, including a large clone of abnormal cells, may progress to AA [40,41]. The exact frequency with which this occurs is not known. One series of 220 patients found an 8 percent incidence of pancytopenia at eight years; the number with AA was not mentioned [2].
On the other hand, patients who present with AA may develop PNH. Before the advent of immunosuppressive therapy for AA, approximately 5 percent of patients developed PNH while about 20 percent of those with PNH had antecedent AA. More recent studies have shown that between 15 and 33 percent of patients receiving antithymocyte serum for the treatment of AA recover with evidence of PNH [42-47]. This phenomenon has also been described after treatment of AA with cyclosporine [48,49].
PNH arising in the setting of aplastic anemia may be a transient phenomenon [50]. The proportion of GPI-deficient PNH cells may remain small, with the predominant clinical manifestations being those of aplasia. In other cases, however, the abnormal clone of cells may increase and predominate the marrow, with the major clinical manifestations being those of PNH [15,40].
Most patients with clinical manifestations of PNH who do not have overt signs of marrow aplasia have evidence of diminished hematopoiesis. Approximately two-thirds exhibit granulocytopenia and/or thrombocytopenia at some time during the course of their disease [51]. These changes are presumably due to deficient production, since the survival of these cells in the circulation is usually normal in the absence of hypersplenism [52,53].
OTHER HEMATOLOGIC DISORDERS — Because PNH is a disorder of the stem cell, it may have other manifestations of stem cell disorders, particularly myelodysplastic syndromes and acute leukemia.
Myelodysplastic disorders — PNH has been described in the setting of myelodysplastic (MDS) or myeloproliferative disorders [54-57], with an incidence ranging from 5 to 9 percent [2,54]. In one patient the PNH cells and the cells characteristic of the dysplasia were derived from the same clone [57]. In a separate study of patients with PNH, cytogenetic abnormalities, and either aplastic anemia or MDS, the abnormal chromosomal patterns were found in the PNH clone in only one of the nine cases studied [58].
Acute leukemia — Some patients with PNH evolve to acute leukemia [56,59-66]. Although an incidence as high as 5 percent has been reported, acute leukemia developed in only 2 to 300 cases (0.7 percent) in two series with long-term follow-up [2,18]. The most common form is acute myelogenous leukemia, in some cases acute erythroleukemia (FAB M6) [64-66], although TdT-positive (usually considered a marker for acute lymphocytic leukemia) and megakaryoblastic leukemia may also occur [61,62].
The onset of leukemia after the diagnosis of PNH usually occurs at about five years, but the reported range is from a few months to 22 years [64,66]. Acute leukemia has occurred in patients who had previously had refractory anemia with excess blasts [59], myelofibrosis [56], or aplastic anemia [67].
In all cases thus far studied, the leukemic clone has evolved from the abnormal PNH clone, since the malignant cells lack GPI-linked proteins [62,68,69]. However, additional genomic abnormalities in these clones are most likely to be responsible for the malignant transformation. In one patient, for example, chromosomal abnormalities appeared to be present in the leukemic clone which did not exist prior to the onset of leukemia [62]. In another case, the PIG-A gene of the leukemic cells appeared to have two defects, but it is not known if these abnormalities were present prior to the onset of leukemia [70]. These studies failed to demonstrate a difference between the PNH line and normal lines in the expression of proto-oncogenes or karyotypic abnormalities.
INFECTIONS — Remarkably little evidence of immune deficiency as defined by a poor response to immunologic stimuli exists in PNH, despite the many abnormalities that can be demonstrated on lymphocytes. This finding may in part be due to the relatively small proportion of abnormal lymphocytes in most cases and/or to the onset of the abnormalities later in life. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Missing cell proteins", section of Lymphocytes).
However, the granulocyte and monocyte abnormalities may result in some predisposition to infection. FcRIII, the low-affinity receptor for IgG, is normally GPI-linked in granulocytes. When this linkage is missing in PNH, the clearance of blood-borne infections should be compromised. However, most clinical reviews suggest that infections most frequently result from granulocytopenia, not from the absence of this receptor.
The lack of effect of the loss of GPI-linked FcRIII may be due to one or both of the following factors: The higher affinity FcRII, present in small amounts on granulocytes, is able to compensate for the loss [71]. Monocytes and macrophages bear the more effective FcRI receptors which bound to the membrane by a transmembrane motif and are not missing in PNH.
ESOPHAGEAL SPASM — Some patients with PNH complain of pressure sensations in the chest and dysphagia concurrent with episodes of hemoglobinuria. When esophageal manometry is used to assess esophageal function, peristaltic waves of great intensity appear to be generated, thereby leading to symptoms. Similar symptoms have been noted in patients who have received injections of modified hemoglobin as "substitute blood."
The pathologic basis for esophageal spasm is unclear. It has been proposed that cell-free hemoglobin in the plasma is able to "sop up" ambient nitric oxide (NO), thereby reducing its effective concentration. Since NO relaxes smooth muscle, its absence may result in excessive contraction of the esophageal musculature. A similar mechanism may account for some of the other symptoms (eg, abdominal pain, erectile dysfunction) observed by PNH patients during episodes of intravascular hemolysis and hemoglobinemia [72,73].
SEXUAL DYSFUNCTION — Many men complain of impotence and erectile dysfunction during hemoglobinuric episodes. The underlying mechanism is unclear, but may again be related to the absence of NO. Relaxation of the vessel walls is necessary for the engorgement of the corpora cavernosa, which may be impossible without NO. (See "Overview of male sexual dysfunction", section on Role of blood flow and nitric oxide)
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