The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018.

OBJECTIVES: A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH). METHODS: All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million. RESULTS: One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively. CONCLUSIONS: This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia.

Hemoglobinuria paroxística nocturna: de Strübing al Eculizumab / Paroxysmal nocturnal hemoglobinuria: from Strübing to Eculizumab

La hemoglobinuria paroxística nocturna (HPN) es un trastorno clonal severo y raro no maligno y adquirido de la célula madre hematopoyética. Es el único trastorno hemolítico adquirido causado por una anomalía de la membrana eritrocitaria como resultado de una mutación somática clonal de un gen, el fosfatidilinositol glucano clase A (PIG-A) situado en el brazo corto del cromosoma X. Se han identificado una serie de proteínas reguladoras del complemento, entre las que se destacan: el factor acelerador de la degradación (CD55) y el factor inhibidor de la lisis reactiva de la membrana (CD 59) deficientes en esta enfermedad. La HPN se clasifica en clásica, asociada a otro trastorno medular y en subclínica. Su diagnóstico se apoya en estudios hematológicos, bioquímicos, pruebas serológicas especiales, estudios eritroferrocinéticos e imagenológicos. La electroforesis de proteínas de membrana de alta resolución y la citometría de flujo multiparamétrica constituyen técnicas de elección para el diagnóstico. El tratamiento de la anemia, de los episodios trombóticos y de las infecciones constituyen los pilares terapéuticos básicos. Dentro de los agentes farmacológicos más utilizados se destacan: los esteroides. los andrógenos, la eritropoyetina recombinante humana y el factor estimulador de colonias granulocíticas. Recientemente, el anticuerpo monoclonal eculizumab ha aumentado la expectativa de vida de estos pacientes con una mejoría de su calidad de vida

Paroxysmal nocturnal hemoglobinuria (PNH) is a non malignant and acquired clonal disease of the hematopoietic stem cell. It is a severe and rare disease. It is the only acquired hemolytic disturbance that is caused for an erythrocyte membrane anomaly. It is a result of a somatic clonal mutation of one gene that is located in the short arm of X chromosome called phosphatidyl inositol glycan class A (PIG-A). Regulated complement proteins are identified: the decay accelerated factor (CD55) and the membrane inhibitor or reactive lysis (CD 59); the abnormal blood cells of PNH have deficiency of these two proteins. PNH is classified in: classic PNH, PNH associated with another bone marrow disturbance and PNH sub clinic. Diagnosis is obtained by hematological, biochemical, kinetics and imagenologics studies and serologic special tests. High resolution membrane protein electrophoresis and flow cytometry are the elective tests. Treatments for anemia, thrombotic episodes and infections are important in the management of these patients. Steroids, androgens, human recombinant erythropoietin and granulocytic colony stimulating factor (CSF-G) are the more used pharmacology agents. Recently, the monoclonal antibody eculizumab has increased the life expectation in these patients with a better quality of life

Paroxysmal nocturnal hemoglobinuria: an historical overview.

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is episodic hemoglobinuria, and it was this feature that captured the attention of European physicians in the latter half of the 19th century, resulting in careful observational studies that established PNH as an entity distinct from paroxysmal cold hemoglobinuria and march hemoglobinuria. Curiosity about the etiology of the nocturnal aspects of the hemoglobinuria led the German physician Paul Strübing to develop the prescient hypothesis that the erythrocytes of PNH are abnormally sensitive to hemolysis when the plasma is acidified during sleep because of accumulation of carbon dioxide and lactic acid as a result of slowing of the circulation. Investigation of the intricate pathophysiology that underlies the abnormal sensitivity of PNH erythrocytes to hemolysis in acidified serum produced a number of remarkable scientific achievements that involved discovery of the alternative pathway of complement, identification of the membrane proteins that regulate complement, discovery of a novel mechanism for attachment of proteins to the cell surface, and identification of the genetic basis of the disease. These discoveries were made steadily over a period of more than 100 years, and each generation of physicians and scientists made important contributions to the field. The mysteries of PNH have been solved in a particularly satisfying way because the precision and orderliness of the solutions made clearly understandable what had seemed at the times prior to resolution to be problems of nearly insurmountable complexity. The history of PNH is an inspirational reminder of the elegant complexity of nature, the rewards of curiosity and the power and beauty of science.

Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired stem cell disorder associated with periodic hemolytic events. This benign clonal disease is caused by abnormalities of the X-linked phosphatidylinositol glycan class A (PIGA) gene and is associated with cytopenias and thrombosis. Although the trilineage of bone marrow elements is affected, involvement of the red blood cell (RBC) line was recognized first due to its abnormal sensitivity to complement-mediated intravascular hemolysis. Totally or partially deficient blood cell membrane proteins include decay accelerating factor (DAF, CD55), membrane inhibitor of reactive lysis (MIRL, CD59), and other proteins attached to the glycophosphatidylinositol (GPI) spine. Stem cell transplantation can be curative in PNH. Diverse laboratory abnormalities observed in PNH include bone marrow hyper- and hypoplasia, hematologic cytopenias, micro- and macrocytosis, decreased leukocyte alkaline phosphatase (LAP), hemoglobin- and hemosiderinuria, as well as associated iron deficiency. The more definitive laboratory tests comprise older biochemical and newer flow cytometric (FCM) procedures. The former group includes the sucrose hemolysis test for screening and Ham's acid hemolysis test for confirmation; the latter group includes FCM analyses of CD55 and CD59, which have recently replaced Ham's test, and FCM quantification of specific GPI-anchor binding using fluorescent-labeled inactive toxin aerolysin (FLAER). FLAER is more sensitive than FCM quantification of antibody-binding to CD59 for PNH diagnosis.

[History of paroxysmal nocturnal hemoglobinuria]. / Historie paroxysmální nocní hemoglobinurie.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal somatic stem cell disorder characterized by intravascular hemolysis, hypercoaguability, and bone marrow failure. Hemolysis is attributed to somatic mutations in the PIG-A gene responsible for the formation of the glycosylphosphatidylinositol (GPI) anchor, that binds CD 59 and CD 55 to the membrane surface. Their absence from the red cell leads to hemolysis whenever complement is activated. PIG-A gene mutations are not sufficient per se for the development of PNH. The history of PNH is a fascinating story depicting the development of our knowledge of the disease since the first clinical description by Paul Strübing in 1882 till the elucidation of the hemolysis on the molecular level. The article describe the historical steps of this process. The pathogenesis of PNH has been significantly elucidated in the last years, but many questions remain to be clarified.

Hemolytic anemia.

We entered the 20th century with only meager understanding of the erythrocyte. We leave this century with a relatively detailed understanding of the metabolism of the erythrocyte, the structure of its membrane, and the basis of genetic disorders that lead to its early demise in hemolytic anemia. Among the immune hemolytic disorders, the conquest of Rh hemolytic disease is one of the important clinical achievements of this century. Hereditary disorders of the membrane generally cause shape changes, such as spherocytosis or ovalocytosis. Paroxysmal nocturnal hemoglobinuria is the result of an acquired (somatic) mutation of PIG-A, an X-linked component of the glycosylphosphatidylinositol (GPI) anchor. Red cell enzyme deficiencies cause hereditary nonspherocytic hemolytic anemia. The mutations that cause the more common of these deficiencies are now well understood at the DNA level. Although much progress has been made, much is still to be learned. In particular, management of both acquired and hereditary hemolytic anemias is still very unsatisfactory. Often the only decision that can be made is whether to perform a splenectomy. In the future it is to be hoped that the knowledge that has been gained about these disorders in this century will make available better therapy to our patients in the next.

Hemoglobinuria Paroxística Nocturna: apuntaciones sobre su historia / Paroxysmal Nocturnal Hemoglobinuria: notes on its history

La hemoglobinuria Paroxística Nocturna (HPN) fue descrita inicialmente por William Gull en 1866, en Londres Inglaterra y representa desde su descripción inicial un buen ejemplo de la evolución de los conceptos y conocimientos, en función del tiempo, en torno a una enfermedad. A William Gull le corresponde el mérito de haber descrito que el pigmento excretado en orina no correspondía a glóbulos rojos (GR). En 1882 Paul Strübing comunicó la siguiente descripción de la HPN. Strübing describió la asociación entre la hemoglobinuria y el ejercicio físico; propuso que la anormalidad residía en los GR, que al circular por los riñones sufrían hemólisis y describió la asociación entre la administración de hierro y las crisis de hemólisis. El nombre de HPN fue establecido en 1928 por Enneking. En 1911, Hijmans-van den Berg demostró que la acidificación de sueros normales o de pacientes con HPN, inducía lisis en los GR de pacientes con HPN. Sin embargo las observaciones de Thomas Hale Ham en 1937, que le permitieron proponer que el defecto de los GR en la HPN consistía en una mayor susceptibilidad a la lisis por el complemento (C'). Pangburn y col. y el grupo de Nicholson-Weller en 1983, describieron que en la HPN existe disminución cuantitativa del factor que acelera la degradación de las convertasas del C' fijadas a la membrana (DAF = "decay accelerating factor", o CD55). En 1987 y 1988, Zalman y col. y Blaas y cols., respectivamente, describen la deficiencia en esta células de la proteina reguladora de la fracción C-59, el inhibidor de membrana de la lisis reactiva o CD59. En 1992, Mahoney y col. y Hirose y su grupo demostraron que en la HPN la síntesis del glucosilfosfatidil inositol (PIG) era defectuosa, lo que en su turno impedía se anclaran las proteinas antes descritas. Estudios realizados por Takeda y col., en la Universidad de Osaka Japón, y publicados en 1993 permitieron clonar el gen PIG (gen PIG-A) e identificaron en la HPN una mutación somática que ocasionaba la pérdida de la función del gen PIG-A. En la actualidad se postula que la clona de HPN emerge como defensa a algún factor externo o interno que inhiba la hematopoyesis normal, pero incapaz de inhibir las células hematopoyéticas deficientes en las protéinas ancladas en el PIG

Evolution of clinical understanding: paroxysmal nocturnal hemoglobinuria as a paradigm.

In recounting the history of the development of knowledge about PNH, the roles of the clinician, the basic scientist, and the clinician-investigator are apparent. Without the observations of the clinicians, the problem could not be posed. Without the contributions from basic science (the biochemistry of complement, the biology of glycosyl-phosphatidylinositol anchors, etc), the information necessary to the solution of the problem would not be available. Without the synthesis of the clinician-investigator, the two elements would not be fused to result in knowledge about the disease.

Paroxysmal nocturnal hemoglobinuria first described in 1882 by Paul Strübing: an example of cooperation between clinical and basic research.

The 100th anniversary of the first description of paroxysmal nocturnal hemoglobinuria by Paul Strübing presents an opportunity to analyze the premises valid for the description of this disease in addition to an attempt at an extensive pathophysiological analysis. Strübing's two papers of 1882 were way ahead of his time, when pathophysiology was just at its beginning, particularly considering the fact that neither Marchiafava, who is still commonly credited wit the first description of this disease (1911) and its recognition as a clinical entity (1928), nor his student Micheli analyzed the PNH syndrome in pathophysiological terms as carefully as Strübing. Both of the former names were given to the disease, which is generally referred to as the Marchiafava-Micheli Anemia. William Crosby, who in 1951 in a historical review of PHN first pointed out the pioneering achievement of Strübing, suggested that it was mainly due to the lack of the right "intellectual climate" at the time that so little attention was paid to his work. Still another important aspect of the early history of PNH will be described in the present paper. The analysis of Strübing's publications leads to the conclusion that he was only able to make his important contribution to medical science because he not only had the appropriate clinical setting but also the scientific backup of the famous physiologist Leonhard Landois and his institute at the University of Greifswald, which is an excellent example of scientific progress through cooperation between a clinician and a research scientist.

[The Donath-Landsteiner hemolysin. The origin of a myth in 20th century medicine]. / Das Donath-Landsteiner-Hämolysin. Die Entstehung eines Mythos in der Medizin des 20. Jahrhunderts.

In the present paper is pointed out that J. Donath and K. L. Landsteiner on no account discovered (as most of modern immunologists are pretending emphatically) the autohemolysin which is still connected with their names; neither can this discovery be attributed to Paul Ehrlich as some modern authors are confirming. The later publications of Donath and Landsteiner following their first famous paper from 1904 which hitherto never was drawn attention to by historians or immunologists clearly demonstrate that both of them thought of a toxin theory in regard to the pathogenesis of paroxysmal cold hemoglobinuria, and yet in 1925 they explicitly denied any kind of immune reaction or autoimmunization being involved in the pathogenesis of this disease. The myth of their supposed discovery was performed by well-known and highly estimated scientists in the field of research in autoimmunity problems based on the psychological well-known motivation to create pioneers and heroes that mark the starting point of their science.