Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

Abstract

In this study, possible adverse effects of pyruvate kinase (PK) deficiency on the maturation of erythroid progenitors were investigated. A 4-year-old Japanese girl with severe PK deficiency underwent splenectomy to reduce her need for blood transfusions. The spleen was examined a histologically, and the hematopoietic progenitors in the spleen were assayed to evaluate the extramedullary hematopoiesis of this PK-deficient subject. The number of hematopoietic progenitors including CFU-GM, BFU-E and CFU-GEMM in the spleen of the PK-deficient patient was much higher than those found in control spleens, indicating enhanced extramedullary hematopoiesis. TUNEL assay demonstrated apoptotic cells in the splenic red pulp of the PK-deficient patient. The expression of 7A6 antigen was detected in cells isolated from spleen and in cells cultured in vitro, but only in those cells that were positive for glycophorin A. These results provide evidence that the metabolic disturbances in PK deficiency affect not only the survival of red cells but also the maturation of erythroid progenitors, which results in premature cell death, i.e., apoptosis. Am. J. Hematol. 74:68-72, 2003.

Cholestasis and Hepatic Failure in a Neonate: A Case Report of Severe Pyruvate Kinase Deficiency

“…[3][4][5][6] ATP deficiency induces irreversible membrane injury, leading to premature erythrocyte destruction in the spleen and liver. 7 It also reduces the erythrocyte capacity to protect itself against destruction from free radicals and oxidative stress.…”

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

“…For instance, direct evidence for ineffective erythropoiesis has been found in splenic tissue from patients with PK deficiency. 31 Nonetheless, the common feature found in patients with PK deficiency are genetic defects in the PKLR gene.…”

Transgenic rescue of hemolytic anemia due to red blood cell pyruvate kinase deficiency

“…20 A TUNEL (terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling) assay was performed using an ApoTag in situ apoptosis detection kit (INTERGEN, Purchase, NY, USA), as described previously. 12 Apoptotic cells isolated from the spleen were analyzed using twocolor flow cytometry, 11 using EPICS XL (BeckmanCoulter, Fullerton, CA, USA) and analyzed with EXPO32 ADC software (Beckman-Coulter). Annexin V-FITC and TER119 monoclonal antibody were obtained from PharMingen and Sigma, respectively.…”

“…9,10 In mature RBC, R-PK is the only detectable PK. We recently demonstrated that R-PK is not only important for mature RBC but also anti-apoptotic molecules for erythroid progenitors both in humans 11 and mice. 12 To establish a gene therapy protocol for PK deficiency, the normal R-PK gene should be introduced into hematopoietic stem cells or erythroid progenitor cells, and the transgene must be activated during erythroid differentiation.…”