Elevated Erythropoietin Research Articles

Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin

AbstractThe most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.

Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice.

While nephrologists often observe reduced hematocrit associated with inhibitors of angiotensin-converting enzyme (ACE), the basis for this effect is not well understood. We now report that two strains of ACE knockout mice have a normocytic anemia associated with elevated plasma erythropoietin levels. (51)Cr labeling of red cells showed that the knockout mice have a normal total blood volume but a reduced red cell mass. ACE knockout mice, which lack tissue ACE, are anemic despite having normal renal function. These mice have increased plasma levels of the peptide acetyl-SDKP, a possible stem cell suppressor. However, they also show low plasma levels of angiotensin II. Infusion of angiotensin II for 2 weeks increased hematocrit to near normal levels. These data suggest that angiotensin II facilitates erythropoiesis, a conclusion with implications for the management of chronically ill patients on inhibitors of the renin-angiotensin system.

Red blood cell survival and kinetics during pregnancy

Profound changes occur during pregnancy in the maternal hematopoietic system in order to meet the needs of the developing fetus and of the mother. By presenting the available data in one review, this review links all known hematopoietic events that occur during normal and certain abnormal pregnancies. Erythropoietin and erythrocyte production are increased during normal pregnancy while erythrocyte mass per unit of body weight remains constant throughout the entire pregnancy, and hemoglobin and hematocrit continuously decrease into the third trimester. Erythrocyte life span is decreased during normal pregnancy due to ‘emergency hemopoiesis’ in response to elevated erythropoietin levels. In preeclampsia, maternal erythrocytes are of similar to non-pregnant state age distribution, while fetal erythrocytes are of younger age distribution than in normal pregnancy. In gestational diabetes, maternal erythrocyte age distribution is similar to that of normal pregnancy. In multifetal pregnancy, maternal erythrocyte age distribution is younger than that of normal pregnancy.

WS17‐11Amniotic fluid erythropoietin concentration and cerebro‐umbilical Doppler flow ratio in diabetic pregnancies and pregnancies complicated by hypertension, pre‐eclampsia or/and intrauterine growth restriction

Subacute or chronic fetal hypoxia is associated with an increase in fetal erythropoietin (EPO) synthesis irrespective of the etiology of hypoxia. Amniotic fluid (AF) EPO level is often elevated in diabetic pregnancies (especially in macrosomic fetuses), and in pregnancies complicated by hypertension (HT), pre‐eclampsia (PE) or/and intrauterine growth restriction (IUGR). It is shown that cerebro‐umbilical arterial flow ratio (RIC/RIU) is often abnormal (less than 1) in the case of fetal hypoxia. We studied AF EPO levels in 29 diabetic pregnancies, 18 pregnancies with HT, PE or/and IUGR and 19 healthy controls. The samples were obtained during the elective amniocenteses in the case of suspected fetal hypoxia or during caesarean sections. Doppler measurements were performed not more than 24 h before amniocenesis. AF EPO levels were significantly elevated in diabetics with abnormal fetal growth (either macrosomia or IUGR) and nondiabetics with HT, PE or/and IUGR as compared with healthy controls or diabetics with normal fetal growth. AF EPO levels of fetuses with normal fetal growth in diabetic mothers were not different from those of healthy controls. There was no correlation between AF EPO levels and RIC/RIU in any of the diabetic or nondiabetic group. However, 5 fetuses had either absent end‐diastolic or reversed umbilical flow. All had elevated AF EPO levels (range 16–15 800 mU/ml). We conclude that both fetal macrosomia and IUGR in diabetic pregnancies seem to cause chronic fetal hypoxia. Normal fetal growth in diabetic pregnancies is not associated with chronic fetal hypoxia. Single measurement of RIC/RIU is of little value in the diagnosis of chronic fetal hypoxia in abnormal pregnancies.

Fetal erythropoietin levels in pregnancies complicated by meconium passage: Does meconium suggest fetal hypoxia?

<h2>Abstract</h2> <b>Objective:</b> We sought to determine whether umbilical cord plasma erythropoietin levels were different in deliveries complicated by meconium passage and to determine whether this response is influenced by gestational age. <b>Study Design:</b> Fetal erythropoietin levels were measured in 203 appropriately grown neonates at 37 to 43 weeks of gestation; among those, 70 had passed meconium. <b>Results:</b> Meconium passage in the entire population was associated with elevated fetal erythropoietin levels (68 vs 31 mIU/mL; <i>P</i> <.001). Cord blood gases, pH, base deficit, and PO₂, as well as the 1- and 5-minute Apgar scores, were not different between the meconium and no-meconium groups. Gestational age and birth weights were significantly higher in the meconium group. Stepwise multiple regression analysis with meconium and gestational age used as the independent variables showed both meconium and gestational age to be independently associated with fetal erythropoietin levels (<i>r</i> = 0.356, F=14.5; meconium, <i>P</i> <.001; gestational age, <i>P</i> <.01). <b>Conclusions:</b> These results suggest that meconium passage can be associated with chronic fetal hypoxia as demonstrated by elevated fetal erythropoietin levels, independent of gestational age. (Am J Obstet Gynecol 2000;183:188-90.)

Fetal erythropoietin levels in pregnancies complicated by meconium passage: Does meconium suggest fetal hypoxia?

Objective: We sought to determine whether umbilical cord plasma erythropoietin levels were different in deliveries complicated by meconium passage and to determine whether this response is influenced by gestational age. Study Design: Fetal erythropoietin levels were measured in 203 appropriately grown neonates at 37 to 43 weeks of gestation; among those, 70 had passed meconium. Results: Meconium passage in the entire population was associated with elevated fetal erythropoietin levels (68 vs 31 mIU/mL; P <.001). Cord blood gases, pH, base deficit, and PO2, as well as the 1- and 5-minute Apgar scores, were not different between the meconium and no-meconium groups. Gestational age and birth weights were significantly higher in the meconium group. Stepwise multiple regression analysis with meconium and gestational age used as the independent variables showed both meconium and gestational age to be independently associated with fetal erythropoietin levels (r = 0.356, F = 14.5; meconium, P <.001; gestational age, P <.01). Conclusions: These results suggest that meconium passage can be associated with chronic fetal hypoxia as demonstrated by elevated fetal erythropoietin levels, independent of gestational age. (Am J Obstet Gynecol 2000;183:188-90.)

Maternal smoking and fetal erythropoietin levels

Objective: To determine the influence of maternal smoking on fetal erythropoietin concentrations in health term pregnancies and test the correlation between cotinine, a biomarker of maternal smoking, and erythropoietin levels in fetuses. Methods: We invited women with healthy term pregnancies to participate in the study, excluding those with conditions previously known to be associated with elevated fetal erythropoietin levels. We recorded demographic data, smoking status, and labor outcome prospectively for each patient. Umbilical venous samples were collected, and serum was stored at −70C to be analyzed later for erythropoietin and cotinine. Umbilical arterial samples were tested for pH and base excess determination. We compared fetal erythropoietin and cotinine between smokers and nonsmokers and examined correlations between erythropoietin and cotinine. Kruskal-Wallis test, t test, median test, and Spearman rank correlation test were used when appropriate. Statistical significance was P < .05. Results: We recruited 35 nonsmokers and 26 smokers and analyzed their samples. The two groups were comparable in demographics and birth outcomes, except for birth weights, which were lower in smokers. Fetal erythropoietin concentrations increased significantly with increasing maternal cigarette consumption, ranging from none to more than 15 cigarettes per day ( P = .03). There was positive correlation between fetal erythropoietin and cotinine concentrations ( r = .41; P = .04), suggesting a dose-response relationship. Conclusion: Fetuses of smokers had increased erythropoietin concentrations that correlate positively with fetal cotinine levels; which suggests an increased risk of subacute hypoxia related to degree of maternal cigarette consumption.

Anaemia caused by asymptomatic Plasmodium falciparum infection in semiimmune African schoolchildren

A cohort of 250 Ghanaian schoolchildren aged 5–15 years was followed clinically and parasitologically for 4 months in 1997/98 in order to study the effect of asymptomatic Plasmodium falciparum infections on haematological indices and bone-marrow responses. Of the 250 children 65 met the predefined study criteria. Thus, 14 children were parasite-free throughout (group 1), 44 had P. falciparum in all blood samples collected but no symptoms of malaria (group 2), and 7 had 1 malaria attack during the study period (group 3). At the end of the study the mean haemoglobin (Hb) level in group 1 was 123 g/L, significantly higher than the value of 114 g/L in groups 2 and 3 ( P < 0·02, adjusted for age and splenomegaly). The low Hb in group 2 was associated with subnormal plasma iron. Low Hb was associated with elevated erythropoietin (EPO) levels, and there was a positive correlation between EPO and reticulocyte counts. However, the reticulocyte response to EPO was more pronounced in uninfected than in infected children, suggesting a partial interference with erythropoiesis in asymptomatic infections. Children with asymptomatic infections had significantly higher plasma levels of tumour necrosis factor than uninfected children (geometric means 50 ng/L and 27 ng/L, respectively, P < 0·001) and this cytokine may contribute to bone-marrow suppression and disturbed iron metabolism. We suggest that asymptomatic malaria leads to a homeostatic imbalance in which erythrocyte loss due to parasite replication is only partially compensated for by increased erythropoiesis. The consequences of the reduced Hb levels on the development and cognitive abilities of children with asymptomatic infections, and the risk of precipitation of iron deficiency, deserve further study and should be considered in malaria control programmes that aim at reducing morbidity rather than transmission.

Familial syndrome of infantile polycythemia with markedly elevated erythropoietin, severe pulmonary hypertension, and intrapulmonary hematopoiesis - an "inappropriate" hypoxic response?

Familial syndrome of infantile polycythemia with markedly elevated erythropoietin, severe pulmonary hypertension, and intrapulmonary hematopoiesis - an “inappropriate” hypoxic response?

An ELISA specific for murine erythropoietin.

Murine recombinant erythropoietin (EPO) was purified from an EPO-producing cell line and used for the production of polyclonal monospecific anti-murine EPO antibodies in rabbits. The anti-mouse EPO antibodies were purified by two affinity chromatography procedures. In order to obtain the most sensitive ELISA, different antibody combinations were tested in the ELISA sandwich assay. The best combination was achieved with an anti-human EPO antibody as coating and the biotinylated anti-murine EPO antibody as detecting antibody. With this sandwich-ELISA a sensitive standard curve in the range of 0.6-30 mU/ml could be established. The assay provides a sensitive and reliable measure of murine EPO in serum and cell culture supernatants ranging from normal to highly elevated EPO levels.

Mild chronic anemia following heart transplantation: a syndrome with prognostic relevance?

The clinical relevance of mild chronic anemia in patients after heart transplantation (HTX) has not yet been demonstrated. Forty-five outpatients who had undergone HTX 2-99 months prior to investigation and who had not received blood transfusions or erythropoietin (EPO) before data acquisition were observed over a period of 37 months. Anemia was found in 36 of the 45 patients and was normocytic, normochromic, and slightly anisocytotic (coefficient of variation = 16 +/- 2, normal 11.5-14.5). Anemic patients showed elevated EPO levels, whereas in nonanemic patients EPO levels were normal. Survival after HTX differed significantly in anemic and nonanemic patients (P < 0.02), with 100% survival in the nonanemic and 85% in the anemic group. Chronic anemia in patients after HTX shows a typical pattern. Even when mild, anemia in patients after HTX seems to be of prognostic value and thus might be an indicator of chronic disorders.

Congenital Erythrocytosis With Elevated Erythropoietin Level

A child who was extensively evaluated for polycythemia is reported. Polycythemia, or erythrocytosis, is seen rarely in children. The mechanisms for congenital and/or familial erythrocytosis are discussed. A 10 1/2-year-old white girl was referred for evaluation of polycythemia, which was detected incidentally during an emergency room visit for a febrile illness. She underwent extensive evaluation to determine the cause of the polycythemia. The literature was reviewed to determine the occurrence of congenital and/or familial erythrocytosis in children and its various causes. Despite extensive evaluation, no specific cause of the erythrocytosis could be determined in our patient. The erythrocytosis appeared to be secondary to an inappropriately elevated serum erythropoietin concentration. Serum erythropoietin rose further after phlebotomy, suggesting nonautonomous hypersecretion. After a review of the literature, we hypothesize that she had an inappropriate erythropoietin expression related to an abnormality in the renal oxygen-sensing mechanism governing erythropoietin synthesis. A discussion of congenital and familial erythrocytosis is presented, and a review of the literature regarding the possible mechanisms causing erythrocytosis is included.

Mild chronic anemia following heart transplantation: a syndrome with prognostic relevance?

Abstract The clinical relevance of mild chronic anemia in patients after heart transplantation (HTX) has not yet been demonstrated. Forty-five outpatients who had undergone HTX 2–99 months prior to investigation and who had not received blood transfusions or erythropoietin (EPO) before data acquisition were observed over a period of 37 months. Anemia was found in 36 of the 45 patients and was normocyte, normochromic, and slightly anisocytotic (coefficient of variation = 16 ± 2, normal 11.5–14.5). Anemic patients showed elevated EPO levels, whereas in nonanemic patients EPO levels were normal. Survival after HTX differed significantly in anemic and nonanemic patients (P < 0.02), with 100% survival in the nonanemic and 85% in the anemic group. Chronic anemia in patients after HTX shows a typical pattern. Even when mild, anemia in patients after HTX seems to be of prognostic value and thus might be an indicator of chronic disorders.

Elevated Umbilical Cord Plasma Erythropoietin Levels in Prolonged Pregnancies

Objective: To determine if umbilical cord plasma erythropoietin levels are elevated in pregnancies that continue beyond their expected date for delivery. Methods: Erythropoietin was measured using an enzyme-linked immunosorbent assay in 124 appropriately grown newborns delivered from 37–43 weeks’ gestation. Each woman had an uncomplicated labor and delivery course without evidence of fetal stress or meconium. The comparison was made between pregnancies ending at 37–40 weeks’ gestation and those at 41–43 weeks’ gestation. Results: There was no difference between the two groups in cord blood gases or Apgar scores at 1 and 5 minutes. Cord plasma erythropoietin levels were significantly higher in pregnancies delivered after 41 completed weeks’ gestation (41 or more weeks: 48.0 ± 7.1 mIU/mL, n = 45 versus 37–40 weeks: 26.1 ± 4.2 mIU/mL, n = 79, P < .001). When compared with pregnancies delivered between 37 and 40 weeks, erythropoietin levels were significantly elevated in pregnancies delivered at either 41, 42, or 43 weeks’ gestation. Conclusion: In pregnancies reaching 41 weeks and beyond, cord plasma erythropoietin levels are significantly increased, indicating altered fetal oxygenation in some of these pregnancies. These results support the current practice of close fetal surveillance of prolonged pregnancies.

Elevated Umbilical Cord Plasma Erythropoietin Levels in Prolonged Pregnancies

Elevated Umbilical Cord Plasma Erythropoietin Levels in Prolonged Pregnancies

Fetuses from Preeclamptic Mothers Show Reduced Hepatic Erythropoiesis

The fetal liver is the main hematopoietic organ during intrauterine life. Morphometrical studies were performed on liver sections to detect changes occurring with intrauterine growth retardation and preeclampsia. Compared with the controls (n = 10), fetuses from preeclamptic mothers showed a severe reduction of erythroid cells by 60% on average (n = 18). Closer examination revealed that the erythroid cells at early stages of differentiation were more affected (80% reduction) than at later stages (55%). Seven out of 18 fetuses from preeclamptic mothers did not show growth retardation but exhibited severely reduced hepatic erythropoiesis. We suggest that the prime factor for impaired red blood cell production is preeclampsia itself rather than intrauterine growth retardation. Regulation of erythropoiesis in utero might depend on the interaction of many hematopoietic growth factors, and preeclampsia might alter the balance. To test this notion, we quantitated erythropoietin in fetal blood and various cytokines in the amniotic fluid. An elevation of erythropoietin and interleukin (IL)-3 levels was seen in babies born under the conditions of preeclampsia, whereas the concentrations of granulocyte/macrophage-colony-stimulating factor (CSF), granulocyte-CSF, and IL-1 beta were reduced, and the levels of IL-6 and IL-8 remained constant. With preeclampsia, a discrepancy between elevation of erythrocyte numbers in peripheral blood and depression of hematopoiesis at the main production site, the fetal liver, is seen. Concomitantly, there is elevation of some but reduction of other hematopoietic cytokines. We envision that during the course of preeclampsia quantitation of hematopoietic growth factors might allow to predict the deterioration of in utero life conditions.

Umbilical cord plasma erythropoietin levels in pregnancies complicated by maternal smoking

Objective: Our goal was to determine whether maternal smoking was associated with elevated umbilical cord erythropoietin, a marker for chronic hypoxia. Study Design: Plasma erythropoietin levels were measured in umbilical cord plasma of 222 newborns. There were 48 mothers who smoked and 174 nonsmokers. Results: When all pregnancies were included, mean cord plasma erythropoietin levels were significantly higher in the smokers (78.0 ± 15.3 mIU/ml) compared with the nonsmoking group (35.2 ± 4.0 mIU/ml; p < 0.005). Regression analysis showed a significant positive correlation between the number of cigarettes smoked per day and cord plasma erythropoietin levels ( r = 0.26, p < 0.0001). Smoking was associated with a significantly elevated risk (relative risk = 2.6, 95% confidence interval 1.7 to 10.9, p < 0.005) of fetal growth restriction. When pregnancies with fetal growth restriction were excluded from the analysis, the difference between the two groups remained significant (smokers 81.3 ± 18.6, n = 38; nonsmokers 24.3 ± 1.4, n = 164; p < 0.03). Conclusions: These results illustrate that smoking during pregnancy is associated with fetal growth restriction and significantly elevated umbilical cord erythropoietin levels. (Am J Obstet Gynecol 1998;178: 433-5.)

Erythropoietin in amniotic fluid as a marker of chronic fetal hypoxia

Objective: To determinate the erythropoietin concentration in amniotic fluid in normal pregnancies and pregnancies with suspected hypoxia. Method: The erythropoietin concentration of 164 samples of amniotic fluid was determined by ELISA. The samples were taken by amniotomy during birth, as well as amniocentesis conducted during prenatal care. Results: A distribution of 1.07–7.29 U/l (10th–90th percentile) within the normal group (n=106) was determined. Significantly elevated erythropoietin levels in amniotic fluid were determined in maternal hypertension (P=0.039) and low birth-weight children (P=0.0032). A correlation with the child's sex could be excluded. Conclusion: Elevated erythropoietin levels in amniotic fluid indicated chronic fetal hypoxia.

Human milk as a potential enteral source of erythropoietin.

In addition to its content of traditional nutrients, milk is a rich source of hormones and peptides, which survive digestion in the neonatal gastrointestinal tract secondary to lower proteolytic activity and increased protein permeability. Previous studies have shown accelerated erythropoiesis or elevated serum erythropoietin (Epo) levels in neonatal (suckling) animals after maternal phlebotomy or maternal hypoxia exposure. We sought to determine whether significant quantities of Epo are present in human milk and whether Epo remains intact under physiologic digestion conditions. Immunoreactive Epo concentrations were determined in 409 human milk samples obtained from mothers of term and premature infants. Samples collected between birth and postpartum d 134 were divided into 11 postpartum day groups. Mean milk-borne Epo concentrations were within the normal range for plasma Epo concentrations and rose with postpartum day (F10,398 = 5.82, p < 0.0001). No differences were observed between milk collected from mothers of premature versus term infants. Estimated weekly human milk-borne Epo intakes approximated the lower range of published parenteral therapeutic doses. In simulated digestion at physiologic pH levels of 3.2, 5.8, and 7.4, milk-borne Epo resisted degradation at 1 and 2 h, compared with baseline. Therefore, we conclude that human milk contains considerable amounts of Epo which resist degradation after exposure to gastric juices at physiologic pH levels. These results support continued investigation into the fate and developmental roles of Epo in human milk.

Polycythemia secondary to focal nodular hyperplasia

An otherwise healthy 14-year-old girl presented with polycythemia and elevated serum erythropoietin. A lesion was identified in the liver by ultrasound scan and computerized axial tomography. The pathology findings of the mass excised by hepatic segmentectomy showed focal nodular hyperplasia that stained positively for erythropoietin by immunohistochemistry. Resection resulted in a cure of the polycythemia with serum erythropoietin, hemoglobin, and hematocrit returning to normal range in subsequent follow-up. To our knowledge, this is the first report of focal nodular hyperplasia resulting in secondary polycythemia.