The variable manifestations of disease in pyruvate kinase deficiency and their management

Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary nonspherocytic hemolytic anemia and results in a broad spectrum of disease. Diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including PK 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 that 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. Therefore, red cell transfusions should be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, that require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease 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 10 PKD experts convened to better define the burden and manifestations of disease. This manuscript summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.