Red Blood Cell Synthesis Research Articles

Fibrinogen-like 1: A hepatokine linking liver physiology to hematology.

A recent study identified the critical contribution of the hepatokine FGL1 to the regulation of iron metabolism during the recovery from anemia. FGL1 is secreted by hepatocytes in response to hypoxia to sequester BMP ligands and repress the transcription of the iron-regulatory hormone hepcidin. This process ensures the proper supply of iron to the bone marrow for new red blood cell synthesis and the restoration of physiological oxygen levels. FGL1 may therefore contribute to the recovery from common anemias and cause iron overload in chronic anemias with ineffective erythropoiesis, such as ß-thalassemia, dyserythropoietic anemia, and myelodysplastic syndromes. However, FGL1 has also been described as a regulator of hepatocyte proliferation, glucose homeostasis, and insulin signaling, as well as a mediator of liver steatosis and immune evasion. Chronic exposure to elevated levels of FGL1 during anemia may therefore have systemic metabolic effects besides iron regulation and erythropoiesis. Here, we are providing an overview of the proposed functions of FGL1 in physiology and pathophysiology.

Iron Status Assessment in Chronic Kidney Disease Patients Preceding Dialysis: An Exploration of Anemia and Iron Deficiency

Objective: The most common kind of anemia, iron deficiency anemia (IDA), is very burdensome for those with chronic kidney disease (CKD). The incidence of IDA rises as renal function deteriorates. The incidence of IDA in CKD patients before the need for dialysis has not been well documented in Pakistan, even though the major cause of anemia in CKD individuals is a shortage of erythrocyte a hormone generated by the kidneys that stimulates red blood cell synthesis. This study's goal is to identify the incidence of IDA in people with kidney failure who are still not receiving dialysis. Methods: We included 188 pre-dialysis CKD patients, ages 18 to 75, of both sexes. Patients with apparent anemia-related reasons were eliminated. During OPD follow-up, it was then established what proportion of patients had IDA in their pre-dialysis CKD. Results: The patients who participated in the research had an average age of 46.03 years, with a standard deviation of 12.24 years. There were 188 patients in all, and 102 of them were men, making up around 54.26% of the sample. The study's 1.2 to 1 male-to-female ratio indicates that men were overrepresented. 73 people, or around 38.83% of the total patients in the research, were found to have iron deficiency anemia (IDA) among people with chronic kidney disease (CKD) who had not yet begun dialysis. Practical Implication: The causes of iron shortage in those with CKD are complicated by several variables, chief among them being decreased nutritional iron consumption and poor gastrointestinal absorption of iron, blood losses brought on by uremia-induced platelet disorder, and persistent inflammation related to CKD. As a result, owing to chronic inflammation causing a reactive rise in ferritin, individuals with CKD have much higher ferritin threshold levels for the absolute iron shortage. As a result, it is advised that patients with CKD before starting dialysis have blood ferritin levels below 100 µg/ml and over 200 µg/ml for those who are already receiving it Conclusions: According to the study, IDA occurs often in pre-dialysis CKD patients. By paying strict attention to the sources of IDA and replacing it, patients' outcomes may be improved. Keywords: anemia, dialysis, chronic kidney disease, erythrocyte, iron deficiency, hormone

Acute cerebral ischemic stroke as a presentation of polycythemia vera: a case report and a review of literature.

In the presenting study, we report a 60-year-old male patient who presented with a right-side weakness for 3 days. After laboratory and brain imaging, he was diagnosed with an acute cerebral infarct affecting the left basal ganglion secondary to PV. PV as the cause of ischemic stroke is a rare condition but can be encountered in clinical practice, and clinicians should be familiar with this combination.

5610611 REAL-WORLD EVIDENCE CHARACTERIZING THE BURDEN OF DISEASE IN ALPHA AND BETA THALASSEMIA PATIENTS IN THE USA: AN INTERIM ANALYSIS

Introduction: Thalassemia is a rare disease caused by impaired red blood cell synthesis of α and/or β globin chains, resulting in ineffective erythropoiesis and chronic hemolytic anemia that may require transfusion therapy. There is a lack of real-world data describing disease burden in thalassemia patients, particularly those with non-transfusion-dependent (NTD) thalassemia and α-thalassemia. This analysis aimed to characterize the burden of disease in patients with thalassemia in the USA. Methods: Data were collected via the Adelphi Thalassemia Disease Specific Programme™, a point-in-time survey of thalassemia-treating physicians and their patients in the USA. Data collection started June 2022 and is ongoing, with data presented here from an interim analysis as of 24th August 2022. Physicians completed a structured online survey for the consecutive patients with α-thalassemia (α-thal) or β-thalassemia (β-thal) seen during the study period. Ethics exemption was obtained from Pearl Institutional Review Board. Results: A total of 28 hematologists/hematologist-oncologists completed surveys for 127 patients, 55 (43%) with α-thal and 72 (57%) with β-thal. Mean patient age was 36.5 and 31.0 years for α-thal and β-thal, and 29 (53%) and 41 (57%) patients were male, respectively. Forty-three (78%) patients with α-thal were trait/carrier (Table 1), and β-thal intermedia (36 [50%]) was the most common type of β-thal. The most frequently physician-reported thalassemia-related symptoms/complications experienced by patients with α-thal and β- thal at the time of data collection were fatigue (28/49 [57%] and 31/60 [52%%], respectively) and anemia (24/49 [49%] and 32/60 [53%], respectively). Seven (13%) patients with α-thal and 10 (14%) with β-thal were considered transfusion dependent (TD) by their physicians while the remaining patients were considered NTD. The most common reason for being considered TD was high risk of patient mortality without transfusions (3/7 [43%]) for α-thal and patient requires multiple transfusions a year due to low blood counts/low hemoglobin (8/10[80%]] for β-thal. Where known, in the 12 months prior to data collection, patients with physician-defined TD α-thal and β-thal received a median of 2.0 (range: 2-12) and 5.0 (range: 2-10) blood transfusions, whilst patients with physician-defined NTD α-thal and β-thal received a median of 0.0 (range: 0-3) and 1.0 (range: 0-3) blood transfusions respectively. Where known, physicians reported that patients with TD α-thal (n=7) and β-thal (n=9) had an average pre-transfusion mean hemoglobin of 10.9 g/dL and 8.4 g/dL and NTD α-thal (n=42) and β- thal (n=59) had a mean hemoglobin of 10.2 g/dL and 9.6 g/dL, respectively. Iron overload due to transfusions was reported in 5/41 (12%) of α-thal and 14/61 (23%) of β-thal patients. Iron chelation was prescribed in 34 (27%) of patients, luspatercept in 23 (18%) and hydroxyurea in 20 (16%). The most frequently reported issues/unmet need for iron chelation was ‘treatment does not reduce the severity of symptoms’ (9/34 [26%]), for luspatercept was ‘patient has to take time off work’ (7/23 [30%]), and for hydroxyurea ‘treatment does not reduce patient’s fatigue’ (7/20 [35%]) patients (Table 2). Conclusion: Despite currently available treatment approaches, both α- and β-thalassemia patients still experience substantial disease burden. Effective and convenient treatment approaches that target fatigue and improve Hb remain an unmet need for many patients.

Legal and Ethical Discourse of Saviour Sibling: How Should Indonesia Respond to this New Trend?

Thalassemia major is a genetic condition characterized by an inefficient synthesis of red blood cells which can be cured by bone marrow transplantation surgery. However, getting a matching donor is a challenging task. Therefore, some people have been using the “saviour sibling” procedure wherein a sibling is born to be a donor for their sibling. This procedure, however, has been raising debate, especially concerning bioethics. Indonesia, a country with a high number of people who suffer from such an abnormal genetic condition, needs to be aware of this procedure and its policy framework. This paper conducts a comparative study in identifying and analyzing how saviour sibling is regulated in countries other than Indonesia. Besides, it discusses the legal and ethical implications of saviour sibling procedures in Indonesia. It is a cross-discipline research that combines legal research in the fields of health law, human rights law, and private law and resources from medical science. The analysis is established by using normative, comparative, and ethical approaches. This study found a disparity in the policy framework between countries because such a procedure is in the grey zone between bioethics and technologies. Nevertheless, no rights are violated because the child would live a life of physical and mental well-being. This procedure also plays a critical role in developing medical technology. In bioethics, the saviour sibling procedure begs whether the conceived sibling is just a means to an end, a mere commodity. In Indonesia, the legal framework on health technology involving human subjects is still relatively lax in regulating saviour siblings. Therefore, this study suggests that Indonesia needs to consider the diverse local wisdom as the foundation of its bioethics in regulating saviour sibling in the future.

Management of Zygomatic Arch Fracture in Polycythemia Vera Patient-A Case Report

Polycythemia vera (PV) is a myeloproliferative neoplastic condition characterized by an unregulated synthesis of red blood cells (RBCs). There is often simultaneous stimulation of the megakaryocytic and myeloid lineages; this causes an increase in the synthesis of white blood cells and platelets2. As a result, there is an increased risk of thrombosis and bleeding. Due to the extensive vascular network of the face and jaw7 and limited surgical access to perform hemostasis, traumatic injuries and surgical procedures are among the most common causes of increased blood loss. Zygomatic bone fracture is one of the most frequent fractures of the facial skeleton. The zygomatic bone is a strong bone that supports the maxilla and the skull base. However, its prominence makes it highly susceptible, mainly when impact occurs on both sides of the face4. Facial bone fractures are associated with 1–11% excess blood loss. These complications have the potential to increase perioperative morbidity and mortality significantly. Adequate precautions must be taken in treating these patients for successful outcomes. The management of patients with PV includes therapeutic preoperative phlebotomy, increased fluid intake, and antiplatelet therapy. This report demonstrates the management of a complex procedure such as maxillofacial trauma in a PV patient with a normal coagulation profile.

Ameliorating effects of probiotics on alterations in iron homeostasis and inflammation in COVID-19.

IntroductionThe coronavirus disease (COVID-19) is caused by the severe acute syndrome coronavirus-2 (SARS-COV-2) and still threatens human life. This pandemic is still causing increased mortality throughout the world. Many recent studies have been conducted to discover the pathophysiology of this virus.Material and methodsHowever, in this narrative review, we attempted to summarize some of the alterations in physiological pathways that were evident in this viral invasion. Excessive inflammation that progresses to cytokine storm, changes in humoral and cell-mediated immunity, and observed alterations in iron metabolism are included in the pathogenesis of the virus. Iron homeostasis disturbances may persist for more than two months after the onset of COVID-19, which may lead to reduced iron bioavailability, hypoferremia, hyperferritinemia, impaired hemoglobin, and red blood cell synthesis. Furthermore, hypoferriemia may impair immune system function. Until now, the traditional treatments discovered are still being tried.ResultsHowever, using probiotics as an adjuvant was shown to have beneficial effects on both iron homeostasis and immunity in COVID-19. Herein, we discussed the possible mechanisms achieved by probiotics to ameliorate iron and immunity changes based on the available literature.ConclusionWe concluded that supplementing probiotics with conventional therapy may improve COVID-19 symptoms and outcomes. Taking into consideration the use of good quality probiotics and appropriate dosage, undesirable effects can be avoided.

Atypical Red Blood Cells Are Prevalent in California Sea Lion Pups Born during Anomalous Sea Surface Temperature Events.

To date, there is limited knowledge of the effects that abnormal sea surface temperature (SST) can have on the physiology of neonate pinnipeds. However, maternal nutritional deficiencies driven by alimentary restrictions would expectedly impact pinniped development and fitness, as an adequate supply of nutrients is essential for growth and proper functioning of all body systems, including red blood cell synthesis and clearance. Here, we investigated red blood cell morphology of California sea lion (CSL) pups from the San Benito Archipelago born during the 2014 and 2015 anomalously high SST events recorded in the northeastern Pacific Ocean. We examined whether atypical erythrocyte morphologies were more common in 2015, when the high SST event was more pronounced, and whether the stable isotope signature of pup fur, as an indicator of maternal feeding strategies, accounted for the number of atypical cells. Various atypical erythrocyte morphologies were more prevalent and more abundant than reference values. Evidence of iron deficiency was found in both years, and only pups born in 2014 showed evidence of active erythropoiesis. Microcytes and reticulocytes were more common in pups with higher isotopic δ13C and lower δ15N values, suggesting a probable relationship between maternal feeding strategies and the effect of climatic anomalies on red blood cell physiology of their pups. As developing pinnipeds require increased oxygen storage capacity for diving and foraging, the presence of atypical erythrocytes could be relevant to CSL pup fitness if the underlying cause is not reverted. This study is a first step to explore the effects that climatic alterations in the marine environment can have on the blood physiology of developing individuals.

Cobalt use and regulation in horseracing: a review

Cobalt, atomic weight 58.9, is a metallic element and environmental substance found in the animal in microgram quantities, predominantly as vitamin B12, but is also a component of at least one mammalian enzyme unassociated with B12. Cobalt is a required trace mineral and has long been administered as a dietary supplement to humans and animals. Cobalt deficiency outside of its requirement in vitamin B12 has not been reported in humans. The administration of cobalt salts was once standard treatment for anaemia in humans, owing to its ability to stimulate red blood cell synthesis. Elemental cobalt acts by stabilising hypoxia inducible factor (HIF-1α), which activates the erythropoietin gene, which in turn increases haemoglobin/red blood cell synthesis, which had led to a presumption that cobalt may be performance enhancing in athletes. Administration of cobalt in amounts sufficient to significantly increase the haematocrit are associated with risk of toxicity in humans, and the only cobalt administration study in horses showed no effect on red blood cell parameters or toxicity. Because of the perception that cobalt administration may enhance athletic performance, racing regulators have recently begun to restrict cobalt use in horseracing which has led to the introduction of cobalt thresholds in several racing jurisdictions. The International Federation of Horseracing Authorities is considering an international regulatory threshold for cobalt of 100 ng/ml in urine, based on studies performed in five different countries. In the United States, the Racing Commissioners International has recently set a primary plasma threshold of 25 ng/ml and secondary threshold of 50 ng/ml. One New York and New Jersey racetrack owner has initiated testing for cobalt and has denied his facilities to trainers whose horses tested positive for excessive quantities of cobalt. This review seeks to summarise what is known about the use of cobalt in horse racing.

Assessment of Maternal Folic Acid and Vitamin B12 Supplement with Foetus Growth

The intrauterine growth & development of foetus is most susceptible stage in the human life cycle. The pregnant woman necessities extra quantities of nearly all essential nutrients to sustenance the growth and development of the foetus. In last few years, the requirement for additional folic acid before and during pregnancy has been extensively discovered, as there is association of it with the neural tube defects. And vitamin B12 is needed for synthesis of red blood cells. The maternal folic acid and vitamin B12 are linked with birth weight & body proportions of their newborn. Hence to get the normal weight baby delivered supplementation of folic acid and vitamin B12 is necessary. On this point the present assesment was designed to assess maternal folate & vitamin B12 status with respect to birth weight & body proportions of their newborn. The level of the folic acid and vitamin B12 was found to be very less in the women’s who had delivered the lower weight babies. This findings are similar to the reported study in the literature. So based on the already reported study and the present study we can conclude that the folic acid & vitamin B12 are two important supplements necessary for the normal baby growth.

Altered erythropoiesis and iron metabolism in carriers of thalassemia.

The thalassemia syndromes (α- and β-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or β-globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both α-thalassemia carriers (ATC) and β-thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis.

β-Thalassemia and Polycythemia vera: Targeting chronic stress erythropoiesis

β-Thalassemia and Polycythemia vera are genetic disorders which affect the synthesis of red blood cells, also referred to as erythropoiesis. Although essentially different in clinical presentation – patients with β-thalassemia have an impairment in β-globin synthesis leading to defective erythrocytes and anemia, while patients with Polycythemia vera present with high hemoglobin levels because of excessive red blood cell synthesis – both pathologies may characterized by lasting high erythropoietic activity, i.e. chronic stress erythropoiesis. In both diseases, therapeutic strategies targeting chronic stress erythropoiesis may improve the address phenotype and prevent secondary pathology, such as iron overload. The current review will address the basic concepts of these strategies to reduce chronic stress erythropoiesis, which may have significant clinical implications in the near future.

Developing glycoproteomic analysis of erythropoietin: towards discovering biomarkers for drug abuse

IntroductionErythropoietin is a glycoprotein hormone that is responsible for regulating the synthesis of red blood cells. Unfortunately, the ability of recombinant human EPO (rhEPO) to enhance haematopoiesis which increases the tissue oxygenation has led to its abuse in sports. The identification of rhEPO is very challenging due to its high similarity with endogenous EPO. EPO and rhEPO have high diversity of glycoforms that have different but overlapped pI. Currently, the standard procedure to detect EPO abuse in urine and blood samples is still utilising gel-based tools which have consistency and sensitivity issues. Glycoproteomic mass spectrometry on the other hand is the new approach in the search for biomarkers to differentiate recombinant EPO from the endogenous one. However, there is still a big gap of knowledge on the glycosylations of EPO that requires extensive profiling. ObjectiveTo perform glycoproteomic profiling of endogenous and recombinant EPO. MethodsNanoLC-Orbitrap-MS/MS was performed on endogenous (uEPO) and several rhEPO (BRP, Mircera, NESP, and Epoetin Delta). The liquid chromatogram was used to illustrate the variations between the molecules in their glycopeptides/peptide retention patterns. Mass spectral data was submitted to a bioinformatic platform for peptide and glycosylation de novo sequencing.MALDI-qTOF-MS/MS was also employed in parallel for glycosylation profiling. Results & DiscussionBRP showed a similar chromatographic pattern as uEPO except for a few distinct peaks. PEGlylated EPO Mircera showed two different regions of chromatographic peaks because the hydrophobic PEGylated peptides were retained longer than the non-PEGlyated peptides. Epoetin Delta and NESP showed even greater variation in the chromatographic pattern compared to uEPO believed to be due to differences in glycosylations and peptide sequence, respectively. Meanwhile, MALDI mass spectrum differential analysis enables the determination of sugar residues attachment to BRP. ConclusionGlycoproteomic mass spectrometric profiling holds the key to better discrimination between endogenous and recombinant EPO for anti-doping purposes.

Out of Balance—Systemic Iron Homeostasis in Iron-Related Disorders

Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism.

Vitamin B-12.

Vitamin B-12.

From kidney development to drug delivery and tissue engineering strategies in renal regenerative medicine

Deterioration of renal function is typically slow but progressive, and therefore renal disease is often diagnosed in a late stage when already serious complaints occur. Ultimately when renal function has dropped below 10%, renal replacement is required. Renal transplantation provides a long-term solution but due to shortage of donor kidneys most patients receive hemodialysis therapy. Although hemodialysis is an effect method to correct disturbances in water and electrolyte balances in the body, it does not substitute for the important endocrine and metabolic renal functions that are critical for homeostasis. Among these functions are, the renal production of renin which controls blood pressure, the secretion of erythropoietin which stimulates the synthesis of red blood cells, and the excretion of protein bound waste products. As a consequence, many dialysis patients remain in poor health. With the development of regenerative medicine, and particularly tissue engineering and novel drug delivery strategies, alternative routes for renal replacement are emerging. Increasing understanding of (stem) cells, growth factors and regeneration in the kidney has contributed to a whole new view on restoration and reconstruction of (parts of) renal tissue that may be used to improve current renal replacement therapies. Here, an overview of critical interactions between cells, growth factors and extracellular matrix molecules in kidney development and regeneration will be described. Ultimately, we will discuss how these interactions can be translated to strategies for in-vivo regeneration and in-vitro reconstruction of the kidney.

Avaliação da anemia em crianças da cidade de Campina Grande, Paraíba, Brasil

A anemia e uma condicao definida como a reducao da concentracao de hemoglobina circulante a um valor inferior ao considerado pela Organizacao Mundial da Saude em13 g/dl, 12 g/dl e 11 g/dl para homens, mulheres e criancas, respectivamente. E considerada a principal consequencia da deficiencia de ferro - um nutriente que atua principalmente na sintese das celulas vermelhas do sangue e no transporte de oxigenio para as demais celulas do corpo. Este trabalho, realizado nos meses de marco e abril de 2007, teve como objetivo avaliar as alteracoes hematologicas e os niveis de ferro serico em criancas de 6 a 59 meses de idade na cidade de Campina Grande-PB. A prevalencia de anemia observada foi de 31,73%, e, dentre as criancas anemicas, 91% apresentaram quadro de anemia leve (Hb 9,0 g/dl). A faixa etaria predominante em que se observou a menor concentracao de hemoglobina foi de 6 a 12 meses (10,26 ± 1,27 g/dl). Considerando-se os varios parâmetros do hemograma para avaliar a etiologia ferropriva entre os anemicos, o RDW (amplitude de distribuicao dos eritrocitos) foi o que mais apresentou especificidade no diagnostico laboratorial da anemia por deficiencia de ferro. Dessa forma, a investigacao laboratorial e essencial para o diagnostico precoce e para o acompanhamento terapeutico eficiente da anemia ferropriva em criancas.

THE HYPOXIC BRAIN

While high altitude mountain climbers know that the human brain can eventually adjust to low oxygen levels, sadly the same is not true in the clinical setting. Within minutes of a stroke or heart failure, delicate neural tissue is already beginning to shut down as the processes that initially

Norepinephrine-mediated hypoxic stimulation of embryonic red cell carbonic anhydrase and 2,3-DPG synthesis.

Hypoxia is the stimulus for activation of red cell carbonic anhydrase II (CAII) and 2,3-diphosphoglycerate (2,3-DPG) synthesis of chick red blood cells during late embryonic development. We have tested whether plasma catecholamines are involved as hormonal mediators, because hypoxia is a well-known stimulus for catecholamine release in mammalian fetuses. Plasma catecholamines were measured in 8- to 16-day-old chick embryos. Plasma levels of norepinephrine (NE) were initially low, but its concentration increased rapidly from 2.7 nM (day 12) to 13.4 nM at day 13 and 25.5 nM at day 16. Epinephrine (E) was not detectable before day 13. Short-term hypoxic exposure of day 11 embryos (1-h incubation at 13.5% O2) increased plasma NE concentration fivefold compared with the controls but had no effect on E. During 15-h in vitro incubation of red blood cells from day 11, addition of 1 microM NE to the incubation medium increased the red cell 2,3-DPG concentration nearly threefold and CAII activity sixfold compared with the control. The CAII activity and 2,3-DPG concentration were also increased when cells were incubated with plasma from late chick embryos. The activation was induced by beta-adrenergic stimulation of adenylyl cyclase. Atenolol and propranolol blocked the effects of NE and embryonic chick plasma. Analysis of de novo protein synthesis ([35S]methionine incorporation) demonstrated that catecholamines stimulate the synthesis of several proteins besides CAII. The results indicate that developmental changes of plasma NE concentration are instrumental in the adenosine 3',5'-cyclic monophosphate-dependent activation of CAII and 2,3-DPG synthesis of red blood cells from late chick embryos.

Control of red cell function of late chick embryos: role of extracellular ATP/AMP and egg size.

Hypoxia is the alleged stimulus for initiation of increase of carbonic anhydrase II (CAII) and 2,3-diphosphoglycerate (2,3-DPG) synthesis of red blood cells from late chick embryos. The PO2-dependent regulation of red cell metabolism is mediated by unknown humoral factors [Million et al., Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R1188-R1196, 1991]. In the present investigation we have analyzed whether interindividual differences in egg size (which result in different surface area-to-mass ratios) affect the timing of initiation of 2,3-DPG and CAII synthesis in late chick embryos. We also investigated the effect of extracellular adenine nucleotides on red cell organic phosphate pattern and O2 affinity to test whether the inhibitory effect of normal or elevated PO2 on 2,3-DPG synthesis and the concomitant increase of ATP (and O2 half-saturation pressure) can be mimicked by these agents. The results show that differences in egg size affect the timing of CAII and 2,3-DPG synthesis, indicating that PO2-dependent regulation of red cell function allows adjustment to the properties of the individual egg. We also found that extracellular ATP, which is rapidly degraded to AMP by red cell ectoenzymes, can alter the red cell phosphate pattern and O2 affinity, i.e., significantly increase red cell ATP, decrease red cell 2,3-DPG and O2 affinity, and thus mimic the effect of normoxia and hyperoxia. These findings suggest that extracellular adenine nucleotides may be involved in the PO2-dependent regulation of embryonic red cell metabolism.