Paroxysmal Nocturnal Hemoglobinuria: Evidence for Monoclonal Origin of Abnormal Red Cells
TL;DR: Paroxysmal nocturnal hemoglobinuria (PNH) was diagnosed in a 26-year-old Nigerian woman who subsequently died of amebic colitis and the red cells bearing the PNH abnormality only had the B variant, suggesting that they all belonged to a single abnormal clone.
About: This article is published in Blood.The article was published on 1970-08-01 and is currently open access. It has received 263 citations till now. The article focuses on the topics: Paroxysmal nocturnal hemoglobinuria & Hemoglobinuria.
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TL;DR: It is reported that PIG-A, which participates in the early step of GPI anchor biosynthesis, is the gene responsible for paroxysmal nocturnal hemoglobinuria.
938 citations
TL;DR: PNH is a chronic disorder that curtails life, and a spontaneous long-term remission can occur, which must be taken into account when considering potentially dangerous treatments, such as bone marrow transplantation.
Abstract: BackgroundParoxysmal nocturnal hemoglobinuria (PNH), which is characterized by intravascular hemolysis and venous thrombosis, is an acquired clonal disorder associated with a somatic mutation in a totipotent hematopoietic stem cell. An understanding of the natural history of PNH is essential to improve therapy. MethodsWe have followed a group of 80 consecutive patients with PNH who were referred to Hammersmith Hospital, London, between 1940 and 1970. They were treated with supportive measures, such as oral anticoagulant therapy after established thromboses, and transfusions. ResultsThe median age of the patients at the time of diagnosis was 42 years (range, 16 to 75), and the median survival after diagnosis was 10 years, with 22 patients (28 percent) surviving for 25 years. Sixty patients have died; 28 of the 48 patients for whom the cause of death is known died from either venous thrombosis or hemorrhage. Thirty-one patients (39 percent) had one or more episodes of venous thrombosis during their illness....
762 citations
TL;DR: The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.
Abstract: The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology. In the rare hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH), somatic mutations result in a deficiency of glycosylphosphatidylinositol-linked surface proteins, including the terminal complement inhibitor CD59, on hematopoietic stem cells. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery. Deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of PNH. A recently developed, humanized monoclonal antibody directed against complement component C5, eculizumab (Soliris; Alexion Pharmaceuticals Inc., Cheshire, CT, USA), blocks the proinflammatory and cytolytic effects of terminal complement activation. The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.
685 citations
623 citations
TL;DR: Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement.
410 citations
Cites background from "Paroxysmal Nocturnal Hemoglobinuria..."
...To cause PNH, PIGA mutations must occur in a self-renewing, hematopoietic stem cell and must achieve clonal dominance.(23,24) The mechanisms leading to the clonal expansion and dominance of PNH stem cells remain a topic of continued investigation....
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References
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TL;DR: Ohno and Hauschka1 showed that in female mice one chromosome of mammary carcinoma cells and of normal diploid cells of the ovary, mammary gland and liver was heteropyKnotic and suggested that the so-called sex chromatin was composed of one heteropyknotic X-chromosome.
Abstract: Ohno and Hauschka1 showed that in female mice one chromosome of mammary carcinoma cells and of normal diploid cells of the ovary, mammary gland and liver was heteropyknotic. They interpreted this chromosome as an X-chromosome and suggested that the so-called sex chromatin was composed of one heteropyknotic X-chromosome. They left open the question whether the heteropyknosis was shown by the paternal X-chromosome only, or the chromosome from either parent indifferently.
3,650 citations
TL;DR: It seems necessary to assume that there is, at least for some period of time during development, randomization of the active and inactive chromosome among the dividing cells of the body.
Abstract: Ohno has shown that in somatic cells of human females, the two X-chromosomes are not alike. One behaves in exactly the same manner as the autosomes, remaining in an extended state during interphase and prophase, while the other assumes a heavily condensed state, forming the Barr sex chromatin body. In male somatic cells, on the other hand, the single X never manifests positive heteropycnosis; it always appears fine and elongated. It seemed to us entirely possible that the female X which condenses during interphase is genetically inactive. The active chromosome could not always be derived either from the mother or from the father, since this would give a pattern of inheritance of sex-linked mutations quite different from the pattern as we know it to exist. It seems necessary, therefore, to assume that there is, at least for some period of time during development, randomization of the active and inactive chromosome among the dividing cells of the body. Women would then be composed of a mosaic of cells, some with a functional paternal X-chromosome, others with a functional maternal X-chromosome. Glucose-6-phosphate dehydrogenase (g-6-pd) deficiency, an inborn error of metabolism of humans,9 represents an ideal test system in which to examine this hypothesis. Many heterozygous females with this disorder have red cell g-6-pd levels which are approximately 50 per cent of normal. If the precursors of a heterozygous female's erythrocytes were, as our hypothesis suggests, a mosaic consisting of some cells with the maternial X-chromosome active, others with the paternal X
471 citations
TL;DR: Both A and B tumors were found in all uteri, consistent with the hypothesis that these tumors arose from single cells.
Abstract: The sex-linked electrophoretic variants A and B of glucose-6-phosphate dehydrogenase were studied in 86 samples of myometrium and 27 leiomyomas from five heterozygous women. All but one sample of myometrium had both A and B bands in equal or nearly equal amounts. In contrast to this, all of the leiomyomas had either an A band or a B band. Both A and B tumors were found in all uteri. These findings are consistent with the hypothesis that these tumors arose from single cells.
355 citations
TL;DR: It is shown that the red cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are unusually susceptible to lysis by hetero- and isoantibodies and complement, and the acidified serum test or Ham's test, is of major importance in the diagnosis of the disease.
Abstract: time that the red cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are unusually susceptible to lysis by hetero- and isoantibodies and complement. These observations have since been confirmed by many other studies using a variety of antibodies (2). The susceptibility of these cells to lysis by antibody and complement has been utilized in the detection of hemolytic antibodies in human serum (3) and in the analysis of the kinetics of hemolysis of human cells by specific antibody and complement (4). The red cells of patients with PNH are also lysed by fresh normal serum, especially when the pH is reduced to 6.5 to 7.0 (5, 6). This reaction, the acidified serum test or Ham's test, is of major importance in the diagnosis of the disease. Lysis by acidified normal serum is abolished when the serum is treated with ammonia or heated to 56° C
271 citations