Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia

Hillman, Robert W.

doi:10.1172/jci106001

Cited by 142 publications

(93 citation statements)

References 21 publications

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“…The mean prephlebotomy steady-state reticulocyte residence time, τ 0 , was estimated at 0.447 (0.100) days (10.7 h) ( Table 1). The estimated τ 0 is similar to other estimates in sheep of 0.61 days and the commonly reported value of 1 day in humans [3,23,32]. From the steady-state value, the reticulocyte residence time increased 2.01-to 2.64-fold during stress erythropoiesis, before dropping below pre-phlebotomy values.…”

Section: Reticulocyte Residence Timesupporting

confidence: 88%

“…From the steady-state value, the reticulocyte residence time increased 2.01-to 2.64-fold during stress erythropoiesis, before dropping below pre-phlebotomy values. The determined maximally increased reticulocyte residence time following a phlebotomy is approximately the same as that previously estimated in vivo in sheep and humans of 4.5-fold and 2-3-fold, respectively [23,32]. It is also very close to the commonly recognized increase in reticulocyte residence time in the systemic in humans due to stress erythropoiesis of 2-3 days [2].…”

Section: Reticulocyte Residence Timesupporting

confidence: 84%

“…The latter is not possible to determine accurately in vivo by only sampling in the systemic circulation. A reticulocyte initially normally exists in the bone marrow of sheep and humans [1,3,32], and therefore cannot be observed until it is released from the marrow into the systemic circulation. Accordingly, the determined drop below baseline reticulocyte residence time post-phlebotomy most likely represents the release of more mature reticulocytes from the bone marrow into the circulation through some rebound/overshoot phenomenon.…”

Section: Reticulocyte Residence Timementioning

confidence: 99%

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Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Freise

Widness

Schmidt

et al. 2007

J Pharmacokinet Pharmacodyn

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Most pharmacodynamic (PD) models of cellular response assume a time-invariant (i.e., constant) cellular disposition despite known changes in the disposition with time, such as the reticulocyte residence time in the systemic circulation during stress erythropoiesis. To account for changes in cellular disposition, a comprehensive PD model that involves endogenous erythropoietin (Epo), reticulocytes, and hemoglobin responses was developed in phlebotomized sheep that considers a time-variant reticulocyte residence time and allows for the simultaneous determination of changes in the cellular disposition and cellular production. Five sheep were phlebotomized to hemoglobin concentrations of approximately 4 g/dl. Epo concentrations, reticulocytes, and hemoglobin concentrations were frequently sampled for 5-7 days prior to and 25-30 days following the phlebotomy. Initial steady-state conditions were assumed and the time-variant reticulocyte residence time in the systemic circulation was semiparametrically represented using a constrained spline function. Hemoglobin production was modeled using a Hill function via an effect site compartment. The initial steady state reticulocyte residence time in the systemic circulation was estimated as 0.477 (0.100) (mean (SD)) days, which maximally increased 2.01-to 2.64-fold higher than the initial steady-state residence time 5.95 (0.899) days post-phlebotomy (P < 0.01). On average, the residence time returned to steady-state values 15.4 (2.36) days post-phlebotomy, which was not significantly different from the initial steady-state value (P > 0.05). The baseline hemoglobin production rate was estimated at 0.0929 (0.0472) g/kg/day and the maximum production rate under stress phlebotomy was estimated at 0.504 (0.0422) g/kg/day. These data indicate that endogenously released Epo under acute anemic conditions can increase hemoglobin production approximately 5-fold. The determined increase in reticulocyte residence time produced under stress erythropoiesis is similar to the commonly reported 2-to 3-fold increase observed in human patients.

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Section: Reticulocyte Residence Timesupporting

confidence: 88%

Section: Reticulocyte Residence Timesupporting

confidence: 84%

Section: Reticulocyte Residence Timementioning

confidence: 99%

See 1 more Smart Citation

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Freise

Widness

Schmidt

et al. 2007

J Pharmacokinet Pharmacodyn

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“…The in vivo determination of the lifespan of RET in blood was determined by studying radioactive iron turnover (5,25). The existing methods of determination of RNA degradation rate involve direct determination of total RNA in a in vitro synchronized population of RET (6,8).…”

Section: Discussionmentioning

confidence: 99%

“…However, to fully understand aging of RET, the bone marrow RET have to be studied in a similar way. This would give a full picture of RET aging during homeostasis and under various nonhomeostatic conditions.Presented in the literature, methods for studying RET physiology often involve a difficult to perform isolation and an in vitro measurement of maturation of a synchronized population using radioactive tracers (5,6,8,25). The in vivo determination of the lifespan of RET in blood was determined by studying radioactive iron turnover (5,25).…”

mentioning

confidence: 99%

Method of determination of the reticulocyte age distribution from flow cytometry count by a structured‐population model

Wiczling

Krzyzanski

2007

Cytometry Pt A

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Background: A flow cytometry count of reticulocytes (RET) provides information about distribution of signal emitted by reticulocyte RNA. A new method of determination of the RNA degradation rate in RET is provided. This technique allows one to determinate the age distribution of RET. Methods: The method is based on a series of flow cytometry counts of cultured RET. From those counts, the changes of signal distribution of RET over time are obtained. The RNA degradation rate of individual RET is then resolved based on changes in the signal distribution of the whole population of cells. The obtained relation between signal and age allows obtaining a RET age density that can be used to characterize RET age distribution and age dependence of processes that control the population dynamics. Results: The total maturation time of RET in rats is 3 days. The median time that a homeostatic RET spends in blood or before it becomes a mature RBC is about 0.6 days, whereas a stress RET needs 0.8 days. Conclusions:The proposed method provides means for studies in vivo RET dynamics using age-structured models. Key terms: reticulocytes; structured population model; RNA degradation; flow cytometry Reticulocytes (RET) are immature red blood cells containing one or more filaments or granules of ribosomal RNA. They are formed during mammalian erythropoiesis through the nuclear exclusion from last stage erythroblasts. Then, after a period of maturation in bone marrow, RET are released into the blood circulation and undergo further differentiation to mature erythrocytes. During that period, RET change from large and motile cells to small, biconcave, discoid cells (1-3). In rats, the RET residence time in the bone marrow is about 17-24 h (4,5). The in vivo disappearance of RET population from blood is linear and takes 30 h (5). In vitro culture studies showed that the RET lifespan in rats is about 2-3 days (5-7). The appearance of young RET in blood, called stress RET, gives an insight into the response of bone marrow to endogenous erythropoietin stimulation, treatment with recombinant human erythropoietin, or other erythropoietic stimuli. Hence, it is used as a relatively fast marker of undergoing erythropoiesis (2). The time stress RET spent in bone marrow can decrease to 6.5 h in rats.The lack of capacity for RNA synthesis in RET causes a progressive decrease in cell content of RNA and is one of the characteristics of maturation of RET and consequently provides means of assessing the RET maturation time. In vitro culture data from rabbits show a linear decline of the RNA content at a rate of about 4% per hour that has been determined over a limited time (8). In rats, an exponential decline with half-life about 24 h was found (9). An analogous decline with half-life of 43 h was reported in humans (10).Enumeration of peripheral RET is primarily done by means of automated counting. For flow cytometry measurements, the RET RNA is labeled with a fluorescence dye and the fluorescence of the dye-RNA complex is recorded (11). In general, youn...

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Hypoerythropoietinemia and Anemia

Douglass¹,

McCall²

1970

Arch Intern Med

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Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia

Cited by 142 publications

References 21 publications

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Method of determination of the reticulocyte age distribution from flow cytometry count by a structured‐population model

Hypoerythropoietinemia and Anemia

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