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The variable manifestations of disease in pyruvate kinase deficiency and their management
Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2229-2239
Hanny Al-Samkari,1 Eduard J. van Beers,2 Kevin H.M. Kuo,3 Wilma Barcellini,4 Paola Bianchi,4 Andreas Glenthøj,5 María del Mar Mañú Pereira,6 Richard van Wijk,7 Bertil Glader8 and Rachael F. Grace9
1Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 2Van Creveldkliniek, University Medical Centre Utrecht, University of Utrecht, Utrecht, the Netherlands; 3Division of Hematology, University of Toronto, University Health Network, Toronto, Ontario, Canada; 4UOS Ematologia, Fisiopatologia delle Anemie, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Department of Hematology, Herlev and Gentofte Hospital, Herlev, Denmark; 6Translational Research in Rare Anaemia Disorders, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain; 7Department of Clinical Chemistry & Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; 8Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, CA, USA and 9Dana/Farber Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
ABSTRACT
Pyruvate kinase deficiency (PKD) is the most common cause of chron- ic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including pyruvate kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell pyruvate and ATP deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin thresh- old. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on dis- ease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
Introduction
Pyruvate kinase deficiency (PKD) is the most common cause of chronic heredi- tary non-spherocytic hemolytic anemia, with a prevalence reported to be between 1:20,000 and 1:300,000 in Caucasian populations and a higher prevalence in areas in which malaria is endemic.1-4 Despite its well-described global geographical dis- tribution, its incidence in large areas of the world remains unknown.
Following the identification by Selwyn and Dacie in 1954 of a patient with hereditary hemolytic anemia whose erythrocytes were not rescued by glucose but were rescued by adenosine triphosphate (ATP) in an ex vivo hemolysis assay, it was
Correspondence:
HANNY AL-SAMKARI
hal-samkari@mgh.harvard.edu
Received: October 21, 2019. Accepted: January 20, 2020. Pre-published: March 12, 2020.
doi:10.3324/haematol.2019.240846 ©2020 Ferrata Storti Foundation
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