Hematology

Clinical manifestations of paroxysmal nocturnal hemoglobinuria

Clinical manifestations of paroxysmal nocturnal hemoglobinuria:

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" and "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Absence of the GPI anchor".)

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".)

DISEASE OVERVIEW — In one large series of patients with PNH, the median age at presentation was 33 years (range: 6 to 82 years), with 14 percent in the age range from 6 to 20 years [2,3] . The clinical manifestations of PNH are primarily related to abnormalities in hematopoietic function, including hemolytic anemia, a hypercoagulable state, bone marrow hypoplasia or aplasia, and progression to myelodysplastic syndrome or acute leukemia [3] .

A large retrospective study of 220 patients, published in 1996, 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.

A further publication from this group, published in 2008 and covering a total of 460 patients followed for a median duration of 6.8 years, indicated a longer median survival time of 22 years [3] . Diagnoses made prior to 1986 and increasing age were associated with worse survival, as was development of thrombosis, bicytopenia, or pancytopenia.

There has been an ongoing effort to correlate the clinical manifestations of the disorder with the biochemical defects that have been defined. This approach has been most successful for understanding the pathogenesis of hemolytic anemia, but has been less successful in understanding the hypercoagulable state and evolution into aplastic anemia [1] . The ability of free hemoglobin liberated during intravascular hemolysis to deplete nitric oxide has shed light on the mechanisms underlying esophageal spasm and sexual dysfunction seen in this condition.

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 two 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 [4] . PNH III cells are destroyed in a random fashion with a total life span of less than 20 days (normal: 110 to 120 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 [5] .
  • The degree of abnormality of the cells. Patients with cells of intermediate abnormality (PNH II cells) 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 [6] .
  • 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 [7] .

 

Renal disease — Intravascular hemolysis in PNH can lead to two forms of renal disease. First, a severe hemolytic episode of whatever cause (often in association with gastroenteritis), with massive hemoglobinuria can cause acute renal failure [8,9] . (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)".)

Second, chronic hemolysis results in iron deposition in the kidneys in almost all patients. The excess iron can be detected by magnetic resonance imaging [10,11]  and, in some cases, by metal detectors at airports. Iron deposition can result in proximal tubular dysfunction [12-14] ; in addition, chronic renal failure due to hemosiderosis and subsequent interstitial scarring can occur in patients with long-standing PNH [12,15,16] . Lesser degrees of chronic kidney disease in patients with PNH may be at least partially reversible following treatment with eculizumab [16] .

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Other consequences of hemolysis — Several other symptoms appear to be directly related to hemolysis and the release into the circulation of the contents of red cells; the association of these symptoms with hemolysis has been made evident by their rapid and complete relief when hemolysis is abrogated by the use of eculizumab. Most patients with PNH have a distressing degree of "fatigue" that is not directly related to the hemoglobin level, is made worse during a hemolytic episode, and is relieved by eculizumab well before a change in hemoglobin level is evident; the cause of this "fatigue" is not known. (See "Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria", section on 'Eculizumab'.)

Several symptoms have been attributed to the sequestration of nitric oxide (NO) by the free hemoglobin released by intravascular hemolysis. NO relaxes smooth muscle and its absence results in excessive contraction of this type of muscle. In PNH, this apparently affects the smooth muscle of the gastrointestinal tract and of several arterial beds. In the GI tract, the most common manifestation is esophageal spasm. Many 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" as well as in healthy volunteers receiving infusion of cell-free hemoglobin [17,18] . (See "Oxygen carriers as alternatives to red cell transfusion", section on 'Gastrointestinal side effects'.)

Patients often complain of cramping abdominal pain of short duration, often in association with a hemolytic episode, which may be due to a similar mechanism affecting the intestinal musculature. This symptom, like the esophageal spasm, is relieved when intravascular hemolysis is stopped by therapy.

Excessive arterial contraction may account for several symptoms. Many men complain of impotence and erectile dysfunction, particularly during hemoglobinuric episodes. 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'.)

A modest reduction in renal function and an element of pulmonary hypertension are frequently seen in patients with PNH. Both of these are improved after treatment with eculizumab. (See "Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria", section on 'Eculizumab'.)

VENOUS THROMBOSIS — PNH is associated with a marked increase in venous thrombosis in the hepatic, other intra-abdominal, and peripheral veins. While this propensity to thrombosis is not well understood, activation of complement on the platelet surface stimulates removal of complement complexes by vesiculation; the resulting circulating microparticles are rich in phosphatidylserine and are highly thrombogenic [19] . (See 'Pathogenesis' below.)

The risk of thrombosis appears to be significantly related to the size of the PNH clone [20] . In two series almost all patients developing thrombosis had more than 50 percent [21]  or more than 61 percent [20]  PNH granulocytes.

This finding may help to explain the different incidences of thrombosis between reports from Asia (<10 percent) [22,23]  and the United States and Europe (40 percent) [2,24] . In a comparative study, we found a significantly higher percentage of PNH granulocytes in patients seen at Duke compared with those seen in Japan (69 versus 43 percent) [21] .

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 [25] . 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 frequently occurs in the intraabdominal veins, particularly the hepatic veins [26-28] . The onset of hepatic vein thrombosis may be insidious or can occur suddenly, frequently in the setting of a hemolytic episode [27] .

Hepatic vein thrombosis was, in the past, detected radiographically by venography. This approach has largely been replaced by MR imaging [10,11] ; CT scanning and ultrasonography also have been used [29] . 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 [11] . 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 [30] .

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 [31] . Surgical removal of the ulcer may lead to resolution of the painful episodes [32] .

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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 [33-35] . 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 (common), epididymis (sometimes confused with orchitis), corpora cavernosa (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 [36] .

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. Membrane fragments from intravascular hemolysis, increased platelet aggregation, enhanced expression of tissue factor, and impaired fibrinolysis all may contribute to this process [37] .

Platelets are able to isolate nascent membrane attack complexes (MACs) in patches that can then be removed by vesiculation [38-40] . 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 [41] . (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 [42] . 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 [43] .

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 [44] . Tissue factor provides the site on cells for activation of the so-called "tissue activation pathway" of coagulation. 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. Absence of the GPI-linked protein tissue factor pathway inhibitor is a likely contributor to abnormality of this procoagulant pathway [45] .

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 [46] .

Arterial thrombosis — Arterial thrombosis has been described in patients with PNH, but is much less common than venous thrombosis [47-49] .

DIMINISHED HEMATOPOIESIS — PNH has been classified among the bone marrow failure syndromes. All patients have evidence of diminished hematopoiesis which can range from diminished colony growth in bone marrow culture to relative reticulocytopenia, granulocytopenia or thrombocytopenia [50,51] . In its most extreme form, PNH is manifest as aplastic anemia (AA). Approximately two-thirds exhibit granulocytopenia and/or thrombocytopenia at some time during the course of their disease [52] . 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 [53,54] .

Patients who present with the clinical manifestations of PNH, including a large clone of abnormal cells, may progress to AA [55,56] . 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. Small numbers of GPI-deficient granulocytes and red cells can be found in up to 70 percent of patients with aplastic anemia [57,58] . In a follow-up five years later, the number of GPI-deficient cells had increased in 17 percent, disappeared in 24 percent, and persisted in 59 percent [59] . 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 [60-65] . This phenomenon has also been described after treatment of AA with cyclosporine [66,67] .

PNH arising in the setting of aplastic anemia may be a transient phenomenon [68] . 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 [21,55] .

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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 [69-72] , with an incidence ranging from 5 to 9 percent [2,69] . Small populations of GPI- granulocytes are found in all types of myelodysplasia (Explore study), particularly in those with refractory anemia (eg, refractory cytopenia with unilineage dysplasia). In this setting, their presence appears to predict an improved prognosis and response to immunosuppressive therapy [73] . In one patient the PNH cells and the cells characteristic of the dysplasia were derived from the same clone [72] . 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 [74] .

Acute leukemia — Some patients with PNH evolve to acute leukemia [71,75-82] . 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 [2,24] . The most common form is acute myeloid leukemia, in some cases acute erythroleukemia (FAB M6) [80-82] , although acute lymphoblastic TdT-positive (usually considered a marker for acute lymphocytic leukemia) and megakaryoblastic leukemia may also occur [77,78] .

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 [80,82] . Acute leukemia has occurred in patients who had previously had refractory anemia with excess blasts [75] , myelofibrosis [71] , or aplastic anemia [83] .

In all cases thus far studied, the leukemic clone has evolved from the abnormal PNH clone, since the malignant cells lack GPI-linked proteins [78,84,85] . 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 [78] . 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 [86] . 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 on '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 [87] .
  • Monocytes and macrophages bear the more effective FcRI receptors which bound to the membrane by a transmembrane motif and are not missing in PNH.

 

SUMMARY — Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder characterized by a defect in the glycosylphosphatidyl-inositol (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). (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Absence of the GPI anchor" and "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Missing cell proteins".)

The clinical manifestations of PNH are primarily related to abnormalities in hematopoietic function, including hemolytic anemia, a hypercoagulable state, bone marrow hypoplasia or aplasia, and progression to myelodysplastic syndrome or acute leukemia.

 

  • Hemolysis: Hemolysis of variable severity is a constant feature of PNH, is mediated by complement activation, and is most pronounced following viral or bacterial infections. (See 'Determinants of hemolysis' above.)
  • Hypercoagulable state: PNH is associated with a marked increase in venous thrombosis in the hepatic, other intra-abdominal, and peripheral veins and, to a lesser extent, arterial thrombosis. (See 'Venous thrombosis' above.)
  • Impaired hematopoiesis: All patients with PNH have evidence of diminished hematopoiesis which can range from diminished colony growth in bone marrow culture to relative reticulocytopenia, granulocytopenia or thrombocytopenia. In its most extreme form, PNH is manifest as aplastic anemia. (See 'Diminished hematopoiesis' above.)
  • Stem cell disorders: PNH, a disorder of the stem cell, may evolve into one of the myelodysplastic syndromes and/or acute leukemia. (See 'Other hematologic disorders' above.

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