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J A Widness

Publications and source records attributed to J A Widness.

At least 37 records · Page 2Linked to original sources
PubMed2000

A pharmacodynamic analysis of erythropoietin-stimulated reticulocyte response in phlebotomized sheep.

The pharmacodynamics (PD) of the reticulocyte response resulting from phlebotomy-induced erythropoietin (EPO) was investigated in adult sheep. The anemia caused by the controlled phlebotomy (Hb < 4 g/dl, t = 0) resulted in a rapid increase in EPO with peak concentrations from 200 to 1400 mU/ml at 0.5 to 3 days generating a delayed reticulocyte response with peak levels from 9.3 to 14.1% at 2.5 to 5.1 days. The PD EPO-reticulocyte relationship is well described by a simple kinetic model involving 3 relevant physiologic parameters: T(1) = lag-time (0.73 +/- 0.32 days, mean +/- S.D.), T(2) = reticulocyte maturation time (5.61 +/- 1.41 days), and k = EPO efficacy coefficient (0.052 +/- 0.048% g/dl mU/ml/day). Accordingly, 0.52% reticulocytes at 10 g/dl Hb level are generated per day at an EPO concentration of 100 mU/ml. The difference between the T(2) parameter in this study and the maturation time reported for humans may be due to interspecies differences or different technique and experimental conditions. The PD transduction appears largely linear in the observed EPO concentration range, indicating a full utilization of EPO without any significant PD saturation. Also, the EPO concentration versus time profiles resulting from the phlebotomy were similar to exogenous EPO profiles resulting from s.c. therapeutic dosing. This study supports the hypothesis that s.c. EPO dosing is more efficacious than i.v. dosing.

Animals↗
PubMed1999

A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans.

The primary mechanism of erythropoietin's (EPO) in vivo elimination and the tissue, or tissues, responsible are unknown. Previous studies indicating that EPO pharmacokinetic (PK) behaviour is nonlinear suggest that EPO elimination takes place by a saturable mechanism. A versatile PK system analysis, the Disposition Decomposition Analysis (DDA), capable of quantification of the Michaelis-Menten parameters, V(m) and k(m) was used to analyze and compare EPO's PK behaviour in newborn sheep and preterm infants. Lambs and infants both demonstrated nonlinear PK behaviour appropriately analyzed with DDA. Compared to preterm infants, lambs had significantly greater (p<0.05) elimination capacity as determined by the V(m) (2789+/-525 versus 1767+/-250 mU/mL per h (mean+/-S.E.), respectively), and larger extrapolated linear clearances (116+/-19.1 versus 21.3+/-1.75 mL/kg per h, respectively) (p<0.01). Lambs also demonstrated significantly larger (p<0.01) degrees of nonlinearity as judged by smaller mean k(m) values (2142+/-258 versus 6796+/-1.007 mU/mL, respectively). Of note, although the DDA does not distinguish what the mechanism of EPO elimination is, enzymatic degradation and receptor-mediated cellular internalization are two possibilities. The in vivo DDA-derived k(m) values were similar to reported in vitro binding affinity k(d) data for erythroid progenitors and cell lines having EPO-R's, i.e. 240-2400 mU/mL. The present study's demonstration that EPO's nonlinear PK behaviour in both sheep and humans can be analyzed by the DDA methodology indicates that the sheep model may be used in invasive studies needed to further characterize the mechanism of EPO elimination.

Animals↗
PubMed1999

Correction of hemorrhage-induced anemia with intra-amniotic iron in the ovine fetus.

OBJECTIVE: This study tested the hypothesis that intra-amniotic iron treatment would enhance fetal red blood cell production after an acute, severe fetal hemorrhage of 40% of estimated blood volume over 2 hours. STUDY DESIGN: Three groups of late-gestation ovine fetuses were studied for 10 days: (1) control fetuses (n = 8), (2) fetuses hemorrhaged on day 3 (n = 11), and (3) similarly hemorrhaged fetuses supplemented with a single bolus of 60 mg of iron injected intra-amniotically immediately after the hemorrhage (n = 7). Statistical analysis was by 3-factor analysis of variance. RESULTS: At 24 hours after hemorrhage, red blood cell mass increased 5% in the control group and was reduced equally in both hemorrhage groups by 32% below day 3 prehemorrhage values. At 7 days after hemorrhage, red blood cell mass increased 27.8% +/- 2.6% (SE) above day 3 baseline values in the control fetuses. In the nonsupplemented hemorrhaged fetuses, red blood cell mass was not different from prehemorrhage values after 7 days (+3.7% +/- 4.1%), whereas red blood cell mass increased by 29.9% +/- 6.1% above prehemorrhage values in the iron-supplemented hemorrhage group (P <.001). CONCLUSION: Intra-amniotic iron supplementation resulted in full restoration of red blood cell mass within 7 days after a large loss of blood in fetal sheep, whereas restoration failed without iron supplementation. Intra-amniotic iron treatment may be of therapeutic value in restoring red blood cell mass in human fetuses with certain types of anemia such as that resulting from fetal or fetomaternal hemorrhage.

Amnion↗
PubMed1999

Cost-effectiveness of a limited-donor blood program for neonatal red cell transfusions.

BACKGROUND: Very-low-birthweight infants have typically been given fresh red cells (RBCs), a practice in which aliquots of RBCs for several infants were issued each day from a single unit. Recently, to limit donor exposures, large volumes of RBCs are reserved for the long-term transfusion support of individual infants. STUDY DESIGN AND METHODS: Medical records were examined retrospectively to assess the costs of a limited-donor program for providing RBC transfusions to very-low-birthweight infants. Costs of multiple- and limited-donor programs were compared by using two samples of 30 consecutive infants treated at The University of Iowa Hospitals and Clinics in 1993 and 1997. Effectiveness was evaluated with respect to the number of donor exposures per infant. RESULTS: The cost, in 1997 dollars, of preparing each small-volume transfusion in the multiple-donor program was $27.86 per transfusion, while that in the limited-donor program was $34.83. This difference was largely attributable to use of white cell reduction in association with the limited-donor program in 1997. Eliminating the costs associated with white cell reduction rendered the costs of the limited- and multiple-donor transfusions comparable. The limited-donor program had donor exposures of 2.0 per infant, while the multiple-donor program had 3.6 exposures per infant (p<0.002). CONCLUSION: The limited-donor blood program reduces donor exposure without adversely affecting costs.

Blood Donors↗
PubMed1999

Measurement of circulating red cell volume using biotin-labeled red cells: validation against 51Cr-labeled red cells.

BACKGROUND: Anemia is a serious problem in the fetus and preterm infant. To investigate the physiology and pathophysiology of anemia and to assess responses to blood transfusions or erythropoietin therapy, measurement of circulating red cell volume would be useful. Because the standard 51Cr method exposes the subject to radiation, a method of measuring circulating red cell volume without radiation exposure, sufficiently sensitive for use in fetuses and infants, was developed. STUDY DESIGN AND METHODS: In 10 healthy adults whose body mass ranged from 56.8 to 115.9 kg, aliquots of autologous red cells were labeled with biotin or with 51Cr, mixed, and transfused intravenously. Circulating red cell volume was measured in posttransfusion blood by quantitating the in vivo dilution of biotinylated red cells. Biotinylated red cells were detected by two methods: 1) 125I-streptavidin and 2) fluorescein-labeled avidin with flow cytometry. RESULTS: Circulating red cell volume measured by 125I-streptavidin detection agreed well with that measured by 51Cr (slope = 1.07, y-intercept = -97, correlation = 0.987). Similarly, circulating red cell volume measured by flow cytometry agreed well with that measured by 51Cr (slope = 1.05, y-intercept = -20, correlation = 0.987). CONCLUSIONS: Circulating red cell volume measured by the use of biotin with either 125I-streptavidin or flow cytometry agrees with that measured by 51Cr. Each system provides a method of performing these studies without exposing the subject to radiation.

Adult↗
PubMed1999

Measurement of red cell survival using biotin-labeled red cells: validation against 51Cr-labeled red cells.

BACKGROUND: Anemia is a serious problem in the fetus and preterm infant.To investigate the physiology and pathophysiology of anemia and to assess responses to blood transfusions and erythropoietin therapy, measurement of circulating red cell survival would be useful. STUDY DESIGN AND METHODS: Because the standard 51Cr method exposes the patient or subject to radiation, a practical, accurate method for measuring red cell survival was developed on the basis of determining the number of biotin-labeled red cells that persist in the circulation by using fluorescein-labeled avidin and flow cytometry. In addition, disappearance of total biotin label was measured by using 125I-streptavidin. Results of each detection method were compared to red cell survival measured by the standard 51Cr method. RESULTS: Biotinylated cells persisted in circulation with life spans approaching normal. Despite near-normal persistence in circulation of the biotin-labeled cells, about one-half of the biotin label left the circulation over the first few weeks, causing early curvilinear disappearance. This observation is consistent with the hypothesis that about one-half of the biotin label leaves the red cells. However, about one-half of the biotin was permanently attached, which produced linear disappearance and approximately normal life span estimates for the linear survival curve appearing after the first few weeks. CONCLUSION: Red cell survival can be measured accurately in humans using enumeration of biotinylated red cells. The method is practical and does not expose the patient to radiation.

Adult↗
PubMed1999

Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers.

The objective of this study was to examine the association of carboxyhemoglobin (COHb) and plasma cotinine levels among pregnant women who smoke cigarettes and their fetuses. Fifteen pregnant women who smoked and their fetuses undergoing cordocentesis had blood samples analysed simultaneously for COHb and cotinine. Linear regression was used to test for associations among study variables. Significant maternal-fetal associations were observed both with COHb (r = 0.72, p = 0.003) and with cotinine (r = 0.96, p = 0.003). Maternal cotinine levels were correlated with maternal and fetal COHb levels (r = 0.96, p = 0.003; r = 0.99, p = 0.0003, respectively). Fetal cotinine levels were correlated with COHb in maternal and in fetal blood (r = 0.81, p = 0.0003; r = 0.88, p<0.0001, respectively). The strong direct associations of maternal and fetal levels of COHb and cotinine indicate that maternal COHb and cotinine measurements may be interpreted as surrogates of fetal COHb levels. However, the specificity, ex vivo stability and ease of measurement of cotinine offer advantages over using COHb in quantifying fetal CO exposure following maternal cigarette smoking.

Adult↗
PubMed1998

Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity in infants with bronchopulmonary dysplasia.

OBJECTIVES: The effects of anemia of prematurity during bronchopulmonary dysplasia (BPD) as well as on the metabolic and erythropoietic functions were determined before and after a transfusion. Fourteen anemic (Hb range: 65-88 gm/L), oxygen dependent (fraction of inspired oxygen < or = 35%), nonventilated, preterm infants with BPD were studied at a postnatal age of 6 +/- 2 weeks. STUDY DESIGN: Cardiac output, heart rate, mean velocity of circumferential fiber shortening, shortening fraction (SF), and stroke volume were assessed by pulsed and continuous wave Doppler echocardiography. Values for resting oxygen consumption, carbon dioxide production, and energy expenditure were obtained by indirect calorimetry. The affinity of oxygenated hemoglobin was determined by a blood oxygen dissociation analyzer. RESULTS: An increased hemoglobin level resulted in a suppression of erythropoietin secretion (p < 0.001), whereas heart rate, cardiac output, stroke volume, and SF decreased (p < 0.05). Weight gain before and after transfusion were similar. Plasma lactate levels decreased from 1.6 +/- 0.3 to 1.2 +/- 0.3. Oxygen consumption, carbon dioxide production, and energy expenditure were not affected. CONCLUSIONS: Anemia of prematurity and BPD increase heart rate, cardiac output, stroke volume, and SF. These hemodynamic compensatory responses are normalized by transfusion.

Adaptation, Physiological↗
PubMed1998

Correction for non-ideal tracer pharmacokinetic disposition by disposition decomposition analysis (DDA).

PURPOSE: Pharmacokinetic (PK) studies assume that the tracer's PK is equivalent to the parent compound. This assumption is often violated. The aim of this work is to present a method enabling the ideal tracer PK, i.e. the PK of the parent compound, to be predicted from the non-ideal tracer. METHODS: The procedure uses a disposition decomposition-recomposition (DDR) that assumes that the labeling mainly changes the elimination kinetics while the distribution kinetics is not significantly affected. In the DDR procedure an elimination rate constant correction factor (kCOR) is determined from a simultaneously fitting to plasma concentration data resulting from an i.v. injection of both the tracer and the parent compound. The correction factor is subsequently used to predict the ideal tracer PK behavior from the disposition function (i.v. bolus response) of the non ideal tracer. RESULTS: The DDR method when applied to plasma level data of erythropoietin (r-HuEPO) and its iodinated tracer (125I-r-HuEPO) from a high (4000U/kg) and a low (400U/kg) dosing of r-HuEPO in newborn lambs (n=13) resulted in excellent agreements in the elimination rate corrected dispositions in all cases (r=0.995, SD=0.0095). The correction factor did not show a dose dependence (p > 0.05). The correction factors were all larger than 1 (kCOR=1.94, SD=0.519) consistent with a reduction in the EPO elimination by the iodination labeling. CONCLUSIONS: The DDR tracer correction methodology produces a better differentiation of the PK of endogenously produced compounds by correcting for the non-ideal PK behavior of chemically produced tracers.

Animals↗
PubMed1997

Fetal plasma iron and restoration of red blood cell mass after hemorrhage of the ovine fetus.

OBJECTIVE: Our purpose was to determine whether the restoration of fetal red blood cell mass after acute hemorrhage of 40% of the fetal blood volume is related to fetal plasma iron concentration. STUDY DESIGN: Ten chronically catheterized ovine fetuses were monitored for 10 days beginning at 125 +/- 1 (SE) days of gestation. After a 3-day control period 40% of the fetal blood was removed over 2 hours at a rate of approximately 1 ml/min. Fetal plasma iron and erythropoietin concentrations, hematocrit, blood volume, and red blood cell mass were measured daily before and for 7 days after fetal hemorrhage. Statistical analysis was by analysis of variance, correlation, and regression. RESULTS: Although blood volume was restored within 3 days of the hemorrhage (101.0% +/- 1.4% of prehemorrhage volume), red blood cell mass was not (81.8% +/- 2.8%). Only 6 of 10 fetuses restored their red blood cell mass to prehemorrhage levels by the end of the 7-day posthemorrhage period. On day 10 red blood cell mass correlated positively with prehemorrhage (r = 0.74, p = 0.015) and posthemorrhage (r = 0.69, p = 0.045) plasma iron concentration and negatively with posthemorrhage erythropoietin concentration (r = -0.68, p = 0.047). CONCLUSION: Fetal plasma iron concentration is an important factor in restoration of fetal red blood cell mass after loss of blood. The negative correlation of erythropoietin concentration with posthemorrhagic red blood cell mass suggests that iron, not erythropoietin, may be the limiting factor in recovery from hemorrhage-induced anemia. Thus iron supplementation of the fetus may be of benefit in the treatment of some types of fetal anemia.

Animals↗
PubMed1997

A tracer interaction method for nonlinear pharmacokinetics analysis: application to evaluation of nonlinear elimination.

A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.

Computer Simulation↗
PubMed1997

Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs.

Chronic phlebotomy is an important mechanism of iron loss in premature infants. We studied inter- and intraorgan iron allocation in 10 twin lamb pairs undergoing an acute 40-50% reduction in red cell volume followed by smaller intermittent phlebotomies over an 11-day period. One twin received no supplemental iron sucrose, while the other received an average daily intravenous dose of iron sucrose of either 1 (n = 3), 2 (n = 3), 5 (n = 3), or 15 (n = 1) mg.kg-1.day-1. The total iron content of the red blood cells, liver, skeletal muscle, heart, and brain was directly related to iron dose up to 2 mg.kg-1.day-1. Tissue iron concentrations remained stable until liver iron was < 200 g/g dry wt, after which iron was preferentially directed to red blood cells over skeletal muscle, heart, and brain. Hemoprotein concentrations decreased proportionately to tissue iron, except myocardial cytochrome c, which remained preserved. Any available iron in phlebotomized, rapidly growing lambs is preferentially directed to red blood cells, and lambs require iron supplementation to maintain tissue iron and hemoprotein concentrations. A decrease in nonheme tissue iron results in the high prioritization of iron among iron-containing proteins.

Anemia↗
PubMed1997

Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin.

We hypothesized that treatment of very low birth weight premature infants with r-HuEPO would increase erythrocyte incorporation and gastrointestinal absorption of iron. Infants with birth weights < or = 1.25 kg and gestational ages < 31 wk were randomized to receive 6 wk of 500 U of r-HuEPO/kg/wk (epo group, n = 7) or placebo (placebo group, n = 7). All infants received daily enteral supplementation with 6 mg of elemental iron per kg. An enteral test dose of a stable iron isotope, 58Fe, was administered after the 1st ("early dosing") and 4th ("late dosing") wk of treatment. Mean (+/-SD) erythrocyte incorporation of the dose of 58Fe administered determined 2 wk after early dosing was significantly greater in the epo group compared with the placebo group (4.4% +/- 1.6 versus 2.0 +/- 1.4%, p = 0.013). In contrast, after late 58Fe dosing, there was no difference between groups in incorporation (3.8 +/- 1.6% versus 5.5 +/- 2.7%). Within the epo group, percentage erythrocyte incorporation of 58Fe did not differ between early and late dosing, whereas in the placebo group it increased 3-fold (p < 0.01). Percentage absorption of 58Fe was not different between the epo and placebo groups after both early dosing (30 +/- 22% versus 34 +/- 8%) and late dosing (32 +/- 9% versus 31 +/- 6%). Absorption of nonlabeled elemental iron and 58Fe were significantly correlated with one another. The percentage of the absorbed 58Fe dose incorporated into Hb was not different between groups. We conclude that, although erythropoietin treatment stimulates erythrocyte iron incorporation in premature infants, it has no effect on iron absorption at the r-HuEPO dose studied.

Double-Blind Method↗
PubMed1997

Rhesus isoimmunization: increased hemolysis during early infancy.

The objective of the present study was to determine whether whole blood carboxyhemoglobin (COHb) and plasma bilirubin, two indicators of hemolysis, are elevated in infants with severe Rh isoimmune hemolytic disease during the first months of life. Beginning at 2 wk of age and continuing monthly for 3 mo, serial blood samples were obtained for COHb, plasma bilirubin, Hb, reticulocyte count, plasma erythropoietin, plasma enzymes, and plasma iron. Because control infants (n = 13) and infants with ABO hemolytic disease (n = 5) did not differ from one another in any of the study parameters, these two groups were combined and compared with infants with the Rh isoimmunization. Infants with severe Rh isoimmune hemolytic disease (n = 13) were found to have significantly lower Hb and significantly higher bilirubin, the COHb fraction divided by the Hb concentration (COHb/Hb), and plasma erythropoietin levels at 2 and 6 wk of age, and reticulocyte counts at 6 wk. The remaining parameters were not different between the control-ABO group and Rh-isoimmune group at any of the study intervals. The study's two primary indicators of hemolysis, plasma bilirubin and COHb/Hb, were significantly correlated with one another in the Rh-immunized group (r = 0.66, p < 0.0001), but not in the combined control-ABO group. Serial Rh antibody concentrations measured in the serum of four neonates with Rh isoimmunization demonstrated a mean half-life of 14.3 d. We speculate that, among infants with severe Rh isoimmune hemolytic disease, elevated total bilirubin levels and COHb/Hb ratios identified in the early weeks of life indicate continuing hemolysis due to persistence of maternal Rh antibodies.

ABO Blood-Group System↗
PubMed1997

The life span of erythrocytes transfused to preterm infants.

This study was made to determine the life span of adult red cells transfused to early preterm infants. Nineteen very preterm infants (birth weight, 878.7 +/- 221 g; gestational age, 26.8 +/- 1.5 wk at birth) were sampled weekly after their last blood transfusion to determine the level (%) of fetal Hb in their circulation. Two microliters of blood were subjected to reverse phase HPLC to separate the alpha, beta, and gamma globin components of their Hbs. The percent of fetal Hb (HbF) was calculated as gamma/gamma + beta x 100. The life span of the adult erythrocytes transfused was defined as the time interval between the transfusion and when the percentage of HbF in the recipient's circulation returns to the HbF levels that exist in the infant's autologous red cells (the maximum post transfusion HbF level). Twelve of the 19 infants were followed until their autologous HbF levels were reached. Their mean adult red blood cell life span was 56.4 +/- 7 d (range: 46-68 d). The results obtained in this study imply that the number of days after a transfusion at which half the cells infused remain in the circulation in a preterm infant is about 30 d.

Adult↗
PubMed1997

Hydroxyl radical generation in oxygen-treated infants.

OBJECTIVE: Because the hydroxyl radical is capable of oxidizing phenylalanine to O-tyrosine, we sought to determine whether increased levels of O-tyrosine are found in urine of infants treated with supplemental oxygen. METHODS: A total of 39 consecutively admitted neonates to an intensive care unit were included. Twenty-seven received supplemental oxygen therapy for respiratory disease, and 12 did not. Urinary O-tyrosine levels were determined on two or more occasions using high-performance liquid chromatography with results expressed as a percentage of the urinary phenylalanine concentration. Using simple and stepwise multiple linear regression analyses, urinary O-tyrosine was examined for associations with relevant clinical conditions and laboratory measurements. RESULTS: Infants supplemented with oxygen showed significantly higher mean +/- SEM urinary O-tyrosine levels (0.40% +/- 0.028) compared with those remaining in room air (0.18% +/- 0.012). Mean daily FIO2 was the clinical and laboratory variable most highly correlated with urinary O-tyrosine (r = 0.66). In the stepwise regression, significant associations were also found for renal fractional sodium excretion and Apgar score at 5 minutes. CONCLUSIONS: Hydroxylation at the O position of phenylalanine, a specific direct marker for the hydroxyl radical attack, was strongly associated with oxygen treatment in neonates. This finding increases our understanding of the pathogenesis of oxygen injury and suggests a basis for developing therapeutic approaches.

Apgar Score↗
PubMed1996

The hematologic and plasma iron responses to severe fetal hemorrhage in the ovine fetus.

OBJECTIVE: We previously reported that the ovine fetus does not significantly increase its red blood cell production rate after a 40% loss of blood in spite of a transient elevation in plasma erythropoietin concentration. In this study we hypothesized that, in response to a more severe loss of blood, the ovine fetus would undergo a sustained rise in plasma erythropoietin concentration and an augmentation in its red blood cell mass expansion rate. STUDY DESIGN: Twelve chronically catheterized fetal sheep (six control and six hemorrhaged) were studied beginning at 126 +/- 1 (SE) days' gestation. Fetal blood volume, plasma volume, red blood cell mass, reticulocyte count, plasma erythropoietin level, and plasma iron level were measured for 10 consecutive days. On days 1, 2, and 3 the hemorrhaged fetuses had an average of 102 +/- 4 ml per day of blood removed at a rate of 1 ml/min for a total of 305 +/- 10 ml of blood removed. Statistical analysis was by one- and three-factor analysis of variance. RESULTS: Control animals had a progressive increase in blood volume, plasma volume, and red blood cell mass throughout the 10-day protocol. Reticulocyte counts and plasma iron and erythropoietin levels did not change. In fetuses at 24 hours after the third hemorrhage blood volume averaged 9.3% below (p = 0.03) and plasma volume averaged 16.4% above (p = 0.04) that in the control animals. Thereafter blood and plasma volumes expanded at rates similar to controls. Erythropoietin increased (p < 0.001) but returned to prehemorrhage values by day 7. Posthemorrhage expansion of the red blood cell mass in the hemorrhaged animals was 1.9 times controls (6.8% +/- 0.9%/day vs 3.5% +/- 0.5%/day, p = 0.003). Fetal reticulocyte counts remained elevated throughout the posthemorrhage observation period (p < 0.001). The fetal plasma iron concentration decreased (p < 0.0001) and remained depressed. The recovery of red blood cell mass and the 10-day mean plasma iron concentration were highly correlated (p = 0.01, r = 0.91). CONCLUSION: The ovine fetus significantly increases its release of red blood cells in response to a severe hemorrhage. Further, the ability of the fetus to restore its red blood cell mass appears to be dependent on the plasma iron concentration.

Animals↗