Paroxysmal nocturnal hemoglobinuria: relation of the clinical manifestations to underlying pathogenic mechanisms

1. Paroxysmal noctural hemoglobinuria is believed to be an acquired diseaseof the hematopoietic system in which abnormal red cells, white cells, and platelets are produced. The lesion of the cells probably involves the stromal proteinsin such a fashion that they are susceptible to the proteolytic effect of a sytem ofnormal plasma enzymes. The severity of the disease depends upon the degree ofsensitivity of a given patient’s blood cells to the plasma hemolytic system.

2. The plasma enzyme system that mediates the destruction of PNH cellsconsists of hemobytic factors and their inhibitors. The most important inhibitoris easily destroyed by thrombin, allowing increased hemolysis. As a consequenceof this, any reaction in the patient that involves the blood coagulation systemis apt to cause a hemolytic crisis.

3. PNH red cells are destroyed intravascularly causing hemoglobinemia.Hemoglobinuria, hemosiderinuria, and abnormalities of iron metabolism aresequels of this reaction.

4. Anemia in PNH is a result of hemolytic disease (short red cell life span)together with a relative bone marrow deficiency.

5. Hemolytic crises in PNH occur when plasma hemolytic activity increases.The intensity of activity depends upon a balance that exists between the hemolytic enzymes in the patient’s plasma and two inhibitory factors. Hemolyticcrises take place when the balance is disturbed in favor of the hemolytic factors.Increased hemolysis at night may be due to changes in the balance of the inhibitor-hemolysin system in addition to the effect on pH that may be produced byretention of CO₂ during sleep. Hemolytic crises have sometimes been due to thetemporary appearance of an autoimmune reaction.

6. Aregenerative crises occur when the bone marrow temporarily suspendsproduction of blood cells. This may result in severe anemia, agranulocyticangina, or both. Purpura is rare in PNH.

7. Chronic leukopenia in PNH is believed to be due to a leukocytic abnormality. The susceptibility to infection of patients with PNH may be related to thedefective white cells.

8. Thrombocytopenia is believed to be due to a platelet abnormality. Theplatelets are prone to agglutinate, and their abnormality may be the basis of thesusceptibility to thrombosis that these patients exhibit.

9. The sensitivity of the platelets to the PNH hemolytic enzymes and thesensitivity of the PNH inhibitor to the action of thrombin suggests that avicious cycle of activity exists between the PNH hemolytic system and thecoagulation system of the blood.

10. Dicumarol is able to impede this cycle. Its use has sometimes relieved theanemia. Dicumarol is of special value in protecting patients with PNH againstthrombotic accidents. Heparin, on the other hand, by acting against the PNHinhibitor system actually causes increased hemolysis.

11. Etiologic factors are discussed, but the etiology of PNH is unknown.

12. As of July 1953, there had been published at least one hundred andsixty-two case reports of PNH.

Submitted on October 22, 1952 Accepted on May 22, 1953     

Paroxysmal nocturnal hemoglobinuria: a case report with a negative Ham presumptive test associated with serum properdin deficiency

1. A case of paroxysmal nocturnal hemoglobinuria (PNH) has been presented in which the Ham presumptive test for PNH was negative.

2. The basis for this false negative test and the atypical results of the Hamcomplete acid hemolysis test for PNH appeared to be due to a loss of the invitro PNH hemolytic activity of the serum associated with a deficiency ofproperdin.

3. The acidosis accompanying the renal failure in this patient did not appear to accelerate the hemolytic process, for there was no apparent reductionof hemolytic activity in vivo when the acidosis was corrected by the administration of sodium bicarbonate.

4. The autopsy observations suggest that the protracted deposition of massive quantities of iron in the kidneys may play a robe in the not uncommonoccurrence of renal disease in PNH.

Submitted on November 12, 1957 Accepted on April 12, 1958     

Paroxysmal nocturnal hemoglobinuria; plasma factors of the hemolytic system

This report demonstrates the role and to some extent the interrelations ofvarious factors that are active in the PNH hemolytic system.

1. Activity of four plasma factors, probably protein in nature, has been demonstrated. Two of these factors are hemolytic against PNH red cells, but not againstnormal red cells. The other two inhibit PNH hemolysis. (a). The heat labilehemolytic factor is water soluble and is therefore present in the soluble fraction ofserum that has been dialyzed against distilled water. It is almost completelydestroyed by heating at 53 C. for 10 minutes. It is slowly inactivated by incubation at 37 C. with 100 units per ml. of thrombin. It is rapidly destroyed by concentrations of thrombin in excess of 200 units per ml. It is inactive unless theheat stable hemolytic factor is also present. (b). The heat stable hemolyticfactor is insoluble in water and is therefore precipitated from serum by dialysisagainst distilled water. It is quite resistant to 100 units per ml. of thrombin andto incubation at 53 C. It is inactive unless the heat labile hemolytic factor is alsopresent. (c). The heat labile inhibitor is insoluble in water and is therefore foundin the insoluble fraction of serum dialyzed against distilled water. It is inactivated by heating at 53 C. for 10 minutes but not by incubation with 100 unitsper ml. of thrombin. (d). The heat stable inhibitor is found in the water-solublefraction of dialyzed serum. It withstands dialysis poorly, but it is not affectedby 30 minutes incubation at 53 C. Incubation at 37 C. with 100 units per ml. ofthrombin for 10 minutes destroys its inhibitory activity. Apparently the inhibitors are not interdependent.

2. Calcium in small amounts is probably essential to the PNH hemolyticsystem. The concentration of calcium that is optimum for hemolysis lies in theneighborhood of 2.5 mM. The optimum is a little less than the amount normallypresent in the plasma. Calcium in excess inhibits hemolysis in vitro, and nohemolysis occurs when the concentration exceeds 25 mM. per liter.

3. Magnesium is also essential to the PNH hemolytic system. As magnesium isadded to the system in vitro hemolytic activity increases until the concentrationexceeds 10 mM. per liter. Amounts greater than that have some dampeningeffect. Magnesium appears to antagonize the heat stable inhibitor of the PNHhemolytic system.

4. Thrombin is involved in this system insofar as the heat stable inhibitor andthe heat labile hemolytic factor may be destroyed by thrombic activity. The inhibitor is rapidly destroyed, the hemolytic factor slowly. Therefore, the sum ofthe reaction to small amounts of thrombin in the PNH hemolytic system is toincrease hemolytic activity.

5. Dilute heparin and protamine increase the activity of the PNH hemolyticsystem in vitro, probably by blocking the two inhibitors. Heparin appears towork against the heat stable inhibitor, protamine against the heat labile inhibitor.

6. The intensity of PNH hemolytic activity whether in vitro or in vivo isprobably related to a balance that exists between the inhibitors and the hemolytic factors. Hemolytic crises may occur when the hemolytic factors are increased or when their antagonists are depressed.

Submitted on July 21, 1952 Accepted on January 31, 1953     

The aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome

Occasionally it is difficult to differentiate paroxysmal nocturnal hemoglobinuria (PNH) from idiopathic aplastic anemia in patients who present with pancytopenia and an aplastic bone marrow. Patients with PNH may not have an abnormal acid hemolysis test, and patients with aplastic anemia may present with evidence of abnormal sucrose lysis, acid hemolysis, and antibody-mediated complement hemolysis. Demonstration of a population of red blood cells which are highly susceptible to antibody-mediated complement lysis makes a diagnosis of PNH probable. Donor red blood cell survival studies, which distinguish intracorpuscular from extracorpuscular hemolytic disorders, permit differentiation of the two disorders.     

The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot

Paroxysmal nocturnal hemoglobinuria (PNH) may arise during long-term follow- up of aplastic anemia (AA), and many AA patients have minor glycosylphosphatidylinositol (GPI) anchor-deficient clones, even at presentation. PIG-A gene mutations in AA/PNH and hemolytic PNH are thought to be similar, but studies on AA/PNH have been limited to individual cases and a few small series. We have studied a large series of AA patients with a GPI anchor-deficient clone (AA/PNH), including patients with minor clones, to determine whether their pattern of PIG-A mutations was identical to the reported spectrum in hemolytic PNH. AA patients with GPI anchor-deficient clones were identified by flow cytometry and minor clones were enriched by immunomagnetic selection. A variety of methods was used to analyze PIG-A mutations, and 57 mutations were identified in 40 patients. The majority were similar to those commonly reported, but insertions in the range of 30 to 88 bp, due to tandem duplication of PIG-A sequences, and deletions of more than 10 bp were also seen. In 3 patients we identified identical 5-bp deletions by conventional methods. This prompted the design of mutation-specific polymerase chain reaction (PCR) primers, which were used to demonstrate the presence of the same mutation in an additional 12 patients, identifying this as a mutational hot spot in the PIG-A gene. Multiple PIG-A mutations have been reported in 10% to 20% of PNH patients. Our results suggest that the large majority of AA/PNH patients have multiple mutations. These data may suggest a process of hypermutation in the PIG-A gene in AA stem cells.     

New insights into paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hemolytic anemia that manifests with abdominal pain, esophageal spasm, fatigue, and thrombosis. The hallmark of PNH at the cellular level is a deficiency in cell surface glycosylphosphatidylinositol anchored proteins; this deficiency on erythrocytes leads to intravascular hemolysis. Free hemoglobin from hemolysis leads to circulating nitric oxide depletion and is responsible for many of the clinical manifestations of PNH, including fatigue, erectile dysfunction, esophageal spasm, and thrombosis. The recently FDA approved complement inhibitor eculizumab has been shown to decrease hemolysis, decrease erythrocyte transfusion requirements, and improve quality of life for PNH patients.     

Impact of magnetic resonance imaging on the diagnosis of abdominal complications of paroxysmal nocturnal hemoglobinuria

Magnetic resonance (MR) imaging is a method of choice for assessing vascular patency and parenchymal iron overload. During the course of paroxysmal nocturnal hemoglobinuria (PNH), it is clinically relevant to differentiate abdominal vein thrombosis from hemolytic attacks. Furthermore, the study of the parenchymal MR signal intensity adds informations about the iron storage in kidneys, liver, and spleen. Twelve PNH patients had 14 MR examinations of the abdomen with spin- echo T1- and T2-weighted images and flow-sensitive gradient echo images. Vessels patency and parenchymal signal abnormalities--either focal or diffuse--were assessed. MR imaging showed acute complications including hepatic vein obstruction in five patients, portal vein thrombosis in two patients, splenic infarct in one patient. In one patient treated with androgens, hepatocellular adenomas were shown. Parenchymal iron overload was present in the renal cortex of eleven patients with previous hemolytic attacks. On the first MR study of the remaining patient with an acute abdominal pain showing PNH, no iron overload was present in the renal cortex. Follow-up MR imaging showed the onset of renal cortex iron overload related to multiple hemolytic attacks. Despite the fact that all our patients were transfused, normal signal intensity of both liver and spleen was observed in three of them. MR imaging is particularly helpful for the diagnosis of abdominal complications of PNH.     

Paroxysmal nocturnal hemoglobinuria: An acquired genetic disease.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by an intravascular hemolytic anemia. Abnormal blood cells lack a series of glycosylphosphatidylinositol (GPI)-anchored proteins. The lack of GPI-anchored complement regulatory proteins, such as decay-accelerating factor (DAF) and CD59, results in complement-mediated hemolysis and hemoglobinuria. In the affected hematopoietic cells from patients with PNH, the first step in biosynthesis of the GPI anchor is defective. At least four genes are involved in this reaction step, and one of them, an X-linked gene termed PIG-A, is mutated in affected cells. The PIG-A gene is mutated in all patients with PNH reported to date. Here, we review recent advances in the understanding of the molecular pathogenesis of PNH.     

Paroxysmal nocturnal hemoglobinuria: current issues in pathophysiology and treatment

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder of the bone marrow that produces intravascular hemolysis, proclivity to venous thrombosis, and hematopoietic failure. Mutation in the PIG-A gene in a stem cell aborts synthesis of glycosyl-phosphoinositol (GPI) anchors and therefore expression of all GPI-anchored proteins on the surface of progeny erythrocytes, leukocytes, and platelets. The hemolytic anemia of PNH is well understood, and erythrocyte susceptibility to complement may be treated with anti-C5a monoclonal antibody. The pathophysiology of PNH cell clonal expansion and its association with immune-mediated marrow failure are not understood, but PNH/aplasia responds to immunosuppressive regimens such as antithymocyte globulin and cyclosporine. The mechanism of thrombosis in PNH is also obscure, but frequently fatal clotting episodes may be prevented by Coumadin (Bristol-Myers Squibb Pharma Co., Wilmington, DE) prophylaxis.     

Production and characterization of lymphoblastoid cell lines with the paroxysmal nocturnal hemoglobinuria phenotype

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder caused by a somatic mutation in a hematopoietic stem cell. The fact that, in some cases, not only myeloid but also lymphoid cells are affected suggests that the mutation has occurred in a multipotent stem cell. By studying the expression of CD59 antigen (membrane inhibitor of reactive lysis) and of decay accelerating factor (DAF) on the lymphocytes of 16 patients with PNH, we found an abnormal population of lymphocytes (with absent CD59 and DAF) in 10 cases. From 4 of these patients we were able to produce Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCLs) that have a PNH phenotype (absent CD59, DAF, and CD48). PNH LCL cells have apparently normal DAF messenger RNA despite not having DAF on their surface. These cell lines will be a valuable resource for further investigation of the defect or defects underlying PNH.     

Markedly high population of affected reticulocytes negative for decay- accelerating factor and CD59 in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) blood cells lack glycosylphosphatidylinositol-anchored membrane proteins such as decay- accelerating factor (DAF) and CD59. This lack is of diagnostic value in PNH. Because reticulocytes in PNH are not yet well characterized, we analyzed reticulocytes obtained from 12 patients with PNH and from 5 healthy volunteers by two-color flow cytometry with a membrane- permeable fluorescent dye, thiazole orange, to identify reticulocytes and monoclonal antibodies to DAF and CD59. Healthy individuals had no affected cells. In all patients, the population of affected reticulocytes negative for DAF and CD59 was markedly higher than the population of affected erythrocytes. Moreover, the population of affected erythrocytes became obviously low in patients who received transfusions and suffered from hemolytic precipitation, whereas the population of affected reticulocytes was unchanged. The persistently high population of affected reticulocytes, despite cytolytic exclusion and an inherently short lifetime, might possibly be explained by relative reticulocytosis caused by an anemia-induced feedback stimulation of erythropoiesis in PNH. Thus, affected reticulocytes could be a reliable marker for the diagnosis of PNH and for the evaluation of erythropoiesis by PNH stem cell.     

Clinical paroxysmal nocturnal hemoglobinuria is the result of expansion of glycosyl-phosphatidyl-inositol-anchored protein-deficient clone in the condition of Deficient Hematopoiesis

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal hematopoietic stem cell disorder in which PIG-A, gene essential for the biosynthesis of the glycosyl-phosphatidyl-inositol (GPI) anchor, is somatically mutated. Absence of GPI-linked proteins from the surface of blood cells is characteristic of the PIG-A mutant (PNH) clone and is also accountable fo certain manifestations, such as intravascular hemolysis. It is unclear how the PNH clone expands and comes to dominate hematopoiesis. In this study, CD34+ cells--committed progenitors (colony-forming cells) representing immature hematopoietic stem cells--and reticulocytes representing the differentiated erythroid cells were quantitated in peripheral blood of patients with PNH. Compared with normal controls (n = 29), CD34+ cell levels were significantly lower in PNH patients who did not have preexisting aplastic anemia (AA) (n = 12) (2.47+/-1.23 versus 4.68+/-1.05 x 106/L, mean +/- standard error; P = .022). PNH patients with precedent aplastic anemia (AA+/PNH) showed markedly low CD34+ cell levels compared with normal control subjects (0.6+/-0.29 versus 4.68+/-1.05 x 10(6)/L; P = .0001). In addition, colony-forming cells from PNH patients were significantly decreased compared with those from normal volunteers (erythroid burst-forming units, 2.8+/-1.2 versu 25.6+/-6.2/5 x 10(5) mononuclear cells; P = .0006; and granulocyte/macrophage colony-forming units, 1.2+/-0.5 versus 13.3+/-3.0/ 5 x 10(5) mononuclear cells; P = .0006). These findings occur in both aplastic and hemolytic types of PNH, suggesting hematopoietic failure in PNH. On the contrary, the numbers of reticulocytes and the reticulocyte production index of PNH patients were significantly higher than those of normal persons and comparable to those from patients with autoimmune hemolytic anemia, indicating accelerating erythropoiesis in PNH. The degree of reticulocytosis correlated well with the proportion of CD59- (PNH) reticulocytes. All of the findings suggest that in the condition of deficient hematopoiesis, the PNH clone arising from the mutated hematopoietic stem cell expands and maintains a substantial proportion of the patient's hematopoiesis.     

Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria

In order to quantitate early erythroid progenitor cells in paroxysmal nocturnal hemoglobinuria (PNH), we have cultured peripheral blood mononuclear cells from 7 PNH patients in a 0.8% methylcellulose medium containing erythropoietin, 2 U/ml. In our experimental conditions, the number of erythroid colonies obtained per 5 X 10(5) mononuclear cells plated was 20.1 +/- 1.9 (SEM) in normal subjects and 2.8 +/- 0.56 (SEM) in PNH patients. In plates from PNH subjects, 38 of 117 showed no growth of erythroid colonies, whereas plates from normal subjects always had colonies. Our findings suggest that PNH patients, despite their hemolytic condition, have a depleted erythroid precursor compartment, and this may play a major role in the pathogenesis of their anemia.     

Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria: Present State and Future Problems

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.     

Highly homologous T-cell receptor beta sequences support a common target for autoreactive T cells in most patients with paroxysmal nocturnal hemoglobinuria

Deficiency of glycosylphosphatidylinositol (GPI)-anchored molecules on blood cells accounts for most features of paroxysmal nocturnal hemoglobinuria (PNH) but not for the expansion of PNH (GPI(-)) clone(s). A plausible model is that PNH clones expand by escaping negative selection exerted by autoreactive T cells against normal (GPI(+)) hematopoiesis. By a systematic analysis of T-cell receptor beta (TCR-beta) clonotypes of the CD8+ CD57+ T-cell population, frequently deranged in PNH, we show recurrent clonotypes in PNH patients but not in healthy controls: 11 of 16 patients shared at least 1 of 5 clonotypes, and a set of closely related clonotypes was present in 9 patients. The presence of T-cell clones bearing a set of highly homologous TCR-beta molecules in most patients with hemolytic PNH is consistent with an immune process driven by the same (or similar) antigen(s)-probably a nonpeptide antigen, because patients sharing clonotypes do not all share identical HLA alleles. These data confirm that CD8+ CD57+ T cells play a role in PNH pathogenesis and provide strong new support to the hypothesis that the expansion of the GPI(-) blood cell population in PNH is due to selective damage to normal hematopoiesis mediated by an autoimmune attack against a nonpeptide antigen(s) that could be the GPI anchor itself.     

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome.

Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-AP-deficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z = 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z = 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z = 2.69). Both the presence of HLA-DR2 and the PNH clone were independent predictors of response but the size of PNH clone did not correlate with improvement in blood count. The results suggest that clonal expansion of GPI-AP-deficient cells is linked to HLA and likely related to an immune mechanism.     

Paroxysmal Nocturnal Hemoglobinuria: From Bench to Bed

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia with highly variable clinical symptoms making the diagnosis and prediction of its outcome difficult. It is caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene that results in deficiency of the glycosylphosphatidylinositol anchor structure responsible for fixing a wide spectrum of proteins particularly CD55 and CD59. The clinical features of this disease arise as a result of complement-mediated hemolysis in unprotected red cells, leukocytes, and platelets as well as the release of free hemoglobin. Patients may present with a variety of clinical manifestations, such as anemia, thrombosis, kidney disease, smooth muscle dystonias, abdominal pain, dyspnea, and extreme fatigue. PNH is an outstanding example of how an increased understanding of pathophysiology may directly improve clinical symptoms and treat disease-associated complications when we inhibit the terminal complement cascade. This topic will discuss PNH overview to assist specialists looking after PNH patients.     

阵发性睡眠性血红蛋白尿症患者粒细胞及血浆尿激酶受体的检测

目的了解阵发性睡眠性血红蛋白尿症(PNH)患者体内尿激酶受体(uPAR)的表达水平,并探讨uPAR检测在PNH诊断中的临床意义.方法用流式细胞仪检测20例PNH患者粒细胞表面uPAR、CD55、CD59的表达水平,并与21例正常人、59例其他贫血患者(18例自身免疫溶血性贫血、6例其他溶血性贫血、26例慢性再生障碍性贫血、9例缺铁性贫血)比较;同时采用免疫放射分析(IRMA)测定PNH患者与正常人血浆可溶性uPAR(suPAR)的水平.结果 20例PNH患者中uPAR 、CD55、CD59表达水平显著降低,且与正常人uPAR表达下限不重叠.在PNH患者中还存在峰型异常[双峰和(或)峰拖尾].而57例其他贫血患者中粒细胞表面uPAR的表达水平无改变.PNH患者血浆suPAR水平为(4.04±2.47 )μg/L,明显高于正常人的(1.73±0.96 )μg/L水平(P＜0.01).PNH患者血浆suPAR水平与粒细胞表面uPAR的表达呈负相关(r=-0.79,P＜0.01).结论 PNH患者粒细胞表面uPAR表达水平降低,而血浆suPAR水平增高,这一变化可作为诊断PNH新的特异性指标.     

Stem cell transplantation for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) represents a rare clonal disorder of hematopoiesis clinically characterized by acquired hemolytic anemia, intravascular hemolysis, hemoglobinuria and frequent occurrence of venous thrombosis. Stem cell transplantation is indicated in patients with severe bone marrow aplasia, repeated massive hemolysis or recurrent life threatening thrombotic complications. Almost 90 transplanted patients with PNH have been published. We report a case of successful allogeneic peripheral blood stem cell transplantation performed in a 24 years old woman with a severe form of PNH with frequent episodes of massive intravascular hemolysis. The patient is now alive completely engrafted 900 days after transplantation without signs of chronic GVHD and without recurrent infections. This case represents the first successfully transplanted patient with PNH in our country.     

Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which venous thrombosis is the most common cause of death. Here we address the risk factors for thrombosis and the role of warfarin prophylaxis in PNH. The median follow-up of 163 PNH patients was 6 years (range, 0.2-38 years). Of the patients, 29 suffered thromboses, with a 10-year incidence of 23%. There were 9 patients who presented with thrombosis, and in the remainder the median time to thrombosis was 4.75 years (range, 3 months-15 years). The 10-year risk of thrombosis in patients with large PNH clones (PNH granulocytes > 50%) was 44% compared with 5.8% with small clones (P <.01). Patients with large PNH clones and no contraindication to anticoagulation were offered warfarin. There were no thromboses in the 39 patients who received primary prophylaxis. In comparison, 56 patients with large clones and not taking warfarin had a 10-year thrombosis rate of 36.5% (P =.01). There were 2 serious hemorrhages in more than 100 patient-years of warfarin therapy. Large PNH granulocyte clones are predictive of venous thrombosis, although the exact cut-off for clone size is still to be determined. Primary prophylaxis with warfarin in PNH prevents thrombosis with acceptable risks.