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Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.

ABSTRACT: Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

SUBMITTER: Planutis A

PROVIDER: S-EPMC5341802 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.

Planutis Antanas A Xue Li L Trainor Cecelia D CD Dangeti Mohan M Gillinder Kevin K Siatecka Miroslawa M Nebor Danitza D Peters Luanne L LL Perkins Andrew C AC Bieker James J JJ

Development (Cambridge, England) 20170201 3

Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the ...[more]

PMID: 28143845

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Project description:BackgroundAnemia is common in critically ill patients and may be exacerbated through phlebotomy-associated iatrogenic blood loss. Differences in phlebotomy practice across patient demographic characteristics, clinical features, and practice environments are unclear. This investigation provides a comprehensive description of contemporary phlebotomy practices for critically ill adults.MethodsThis is an observational cohort study of adults ≥18 years of age requiring intensive care unit (ICU) admission between January 1, 2019, and December 31, 2019, at a large academic medical center. Descriptive statistics were utilized to summarize all phlebotomy episodes throughout hospitalization, with each phlebotomy episode defined by unique peripheral venous, central venous, or arterial accesses for laboratory draws, exclusive of finger sticks. Secondarily, financial costs of phlebotomy and the relationships between phlebotomy practices, hemoglobin concentrations, and red blood cell (RBC) transfusions were evaluated.ResultsA total of 6194 patients were included: 59% were men with a median (interquartile range) age of 66 (54-76) years and median ICU and hospital durations of 2.1 (1.4-3.9) and 7.1 (4.3-11.8) days, respectively. The median number of unique laboratory draws was 41 (18-88) throughout hospitalization, with a median volume of 232 (121-442) mL, corresponding to 5.2 (2.6-8.8) draws and 29 (19-43) mL per day. Waste (ie, discard) volume was responsible for 10.8% of total phlebotomy volume. Surgical patients had a higher number of phlebotomy episodes and greater total phlebotomy volumes compared to nonsurgical patients. Phlebotomy practices differed across ICU types, with the greatest frequency of laboratory draws in the cardiac surgical ICU and the greatest daily phlebotomy volume in the medical ICU. Across hospitalization, ICU environments had the greatest frequency and volumes of laboratory draws, with the least intensive phlebotomy practice observed in the general hospital wards. Patients in the highest quartile of cumulative blood drawn experienced the longest hospitalizations, lowest nadir hemoglobin concentrations, and greatest RBC transfusion utilization. Differences in phlebotomy practice were limited across patient age, gender, and race. Hemoglobin concentrations declined during hospitalization, congruent with intensity of phlebotomy practice. Each 100 mL of phlebotomy volume during hospitalization was associated with a 1.15 (95% confidence interval [CI], 1.14-1.17; P < .001) multiplicative increase in RBC units transfused in adjusted analyses. Estimated annual phlebotomy costs exceeded $15 million (approximately $2500 per patient admission).ConclusionsPhlebotomy continues to be a major source of blood loss in hospitalized patients with critical illness, and more intensive phlebotomy practices are associated with lower hemoglobin concentrations and greater transfusion utilization.

Dataset Information

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.

Publications

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.

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