losartan-potassium and Hemorrhage

Orthopedic surgical procedures, especially in the lower limbs, are associated with a high risk of massive bleeding and, consequently, the development of anemia and the need for blood transfusions and its preparations. This creates the need to look for effective methods of prevention and treatment of anemia that will be safe for the patient and reduce the cost of treatment. One of the most common methods of limiting the allogenic blood usage in orthopedic procedures is the use of autologus transfusions. In addition to many benefits, they may contribute to the patient's anemia, which is a serious health problem in the post-operative period. Analyzed data from the literature indicate that the use of recombinant human erythropoietin significantly reduces the need for blood transfusion in the perioperative period and may reduce the cost of treatment.

Topics: Anemia; Erythropoietin; Hemorrhage; Humans; Orthopedic Procedures; Perioperative Period; Recombinant Proteins

Integrating evidence from randomized controlled trials (RCTs) into patient care is needed to optimize patient outcomes. Transfusion support during allogeneic hematopoietic cell transplantation (alloHCT) is a cornerstone of essential supportive care, yet optimal transfusion practices remain unclear.. A scoping review of RCTs in alloHCT was conducted and 14 full-length articles on transfusion practice were identified that reported clinical outcomes after alloHCT.. Eight RCTs compared various interventions related to platelet (PLT) transfusion, addressing product storage duration, dosage, and threshold for transfusion. Restrictive prophylactic PLT transfusion strategies were successful at reducing PLT consumption without impacting clinical outcomes. One study, however, reported increased bleeding associated with a strategy whereby patients did not receive prophylactic PLT transfusions. One study of thrombopoietin was associated with reduced PLT transfusion events but no difference in clinical outcomes compared to placebo. Six RCTs examined the utility of recombinant erythropoietin (EPO) in reducing red blood cell (RBC) transfusion dependence. Four trials reported an increase in hemoglobin levels while five studies demonstrated a reduction in RBC utilization; however, clinical outcomes were variably reported and no differences were identified. There were no RCTs examining RBC transfusion strategies, plasma transfusion, or plasma-derived protein administration.

Topics: Erythropoietin; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Platelet Transfusion; Pre-Exposure Prophylaxis; Randomized Controlled Trials as Topic; Thrombopoietin; Transplantation, Homologous; Treatment Outcome

Topics: Acute Lung Injury; Adult; Anemia; Blood Preservation; Blood Specimen Collection; Brain Injuries; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Myocardial Ischemia; Nervous System Diseases; Sepsis; Shock; Stroke; Subarachnoid Hemorrhage

Multiple and complex abnormalities of hemostasis are revealed by laboratory tests in such common diseases as cirrhosis and end-stage renal insufficiency. Because these abnormalities are associated with a bleeding tendency, a causal relationship is plausible. Accordingly, an array of transfusional and nontransfusional medications that improve or correct these abnormalities is used to prevent or stop hemorrhage. However, recent data indicate that the use of hemostatic drugs is scarcely justified mechanistically or clinically. In patients with uremia, the bleeding tendency (mainly expressed by gastrointestinal bleeding and hematoma formation at kidney biopsy) is reduced dramatically by the improvement of anemia obtained with the regular use of erythropoietin. In cirrhosis, the most severe and frequent hemorrhagic symptom (acute bleeding from esophageal varices) is not explained by abnormalities in such coagulation screening tests as the prothrombin and partial thromboplastin times, because formation of thrombin the final coagulation enzyme is rebalanced by low naturally occurring anticoagulant factors in plasma that compensate for the concomitant decrease of procoagulants. Rebalance also occurs for hyperfibrinolysis and platelet abnormalities. These findings are consistent with clinical observations that transfusional and nontransfusional hemostatic medications are of little value as adjuvants to control bleeding in advanced liver disease. Particularly in uremia, but also in cirrhosis, thrombosis is becoming a cogent problem.

Topics: Anemia; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Coagulants; Erythropoietin; Fibrosis; Hemorrhage; Hemostasis; Humans; Kidney Diseases; Liver Diseases; Partial Thromboplastin Time; Risk Factors; Uremia

The essential biological role of erythropoietin (EPO) in maintaining erythrocyte mass has been well understood for many years. Although EPO is required for the maturation of red cells, it also has strong procoagulant effects on the vascular endothelium and platelets, which limit erythrocyte losses after hemorrhage. Like other members of the type 1 cytokine superfamily, EPO has multiple biological activities. For the past 10 years, multiple investigators have shown that EPO acts as a locally produced antagonist of proinflammatory cytokines that are generated by the innate immune response in response to infection, trauma, or metabolic stress. Specifically, EPO inhibits apoptosis of cells surrounding a locus of injury, reduces the influx of inflammatory cells, and recruits tissue-specific stem cells and endothelial progenitor cells. Available evidence suggests that these multiple, nonerythropoietic effects of EPO are mediated by a tissue protective receptor (TPR) that is distinct from the homodimeric receptor responsible for erythropoiesis. Notably, activation of the TPR requires a higher concentration of EPO than is needed for maximal erythropoiesis. Unfortunately, these higher concentrations of EPO also stimulate hematopoietic and procoagulant pathways, which can cause adverse effects and, therefore, potentially limit the clinical use of EPO for tissue protection. To circumvent these problems, the EPO molecule has been successfully modified in a variety of ways to interact only with the TPR. Early clinical experience has shown that these compounds appear to be safe, and proof of concept trials are ready to begin.

Topics: Animals; Apoptosis; Coagulants; Erythrocytes; Erythropoiesis; Erythropoietin; Hemorrhage; Humans; Hypoxia; Inflammation; Ischemia; Malaria, Cerebral; Neoplasms; Signal Transduction; Stem Cells; Thrombosis

Because of the firm refusal of transfusion of blood and blood components by Jehovah's Witnesses, the management of Jehovah's Witness patients with severe bleeding is often complicated by medical, ethical, and legal concerns. Because of a rapidly growing and worldwide membership, physicians working in hospitals should be prepared to manage these patients. Appropriate management of a Jehovah's Witness patient with severe bleeding entails understanding of the legal and ethical issues involved, and meticulous medical management, including treatment of hypovolemic shock, local hemostatic interventions, and administration of prohemostatic agents, when appropriate. In addition, high-dose recombinant erythropoietin in combination with supplemental iron may enhance the speed of hemoglobin synthesis.

Topics: Acute Disease; Adult; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Contraindications; Emergencies; Erythropoietin; Hemorrhage; Hemostatic Techniques; Humans; Informed Consent; Jehovah's Witnesses; Phlebotomy; Recombinant Proteins; Shock; Treatment Refusal; Unconsciousness; Vitamin K

Blood transfusions and blood products are often given as a life-saving measure in patients with critical illness. However, some patients, such as Jehovah's Witnesses, may refuse their administration due to religious beliefs. Jehovah's Witnesses accept most available medical treatments, but not blood transfusions or blood products due to their religion's interpretation of several passages from the Bible. Since recombinant human erythropoietin (rHuEPO) became available, several cases have been reported in which rHuEPO was successfully administered to critically ill Jehovah's Witnesses. Administration of rHuEPO in combination with other blood conservation techniques has been shown to increase hemoglobin levels and survival in patients who experienced trauma, burns, general surgery, or gastrointestinal hemorrhage. We performed a literature search of the MEDLINE and International Pharmaceutical Abstracts databases of rHuEPO therapy in the Jehovah's Witness population. Fourteen cases were identified in which rHuEPO was administered to Jehovah's Witnesses who required the drug for critical care resuscitation as an alternative to blood products. In each clinical situation, rHuEPO enhanced erythropoiesis; however, time to the start of treatment, dosages, route of administration, and treatment duration varied widely. Supplementation with adjunctive agents, such as iron, folic acid, and vitamin B12, was also beneficial. Use of rHuEPO in Jehovah's Witnesses may provide an alternative to blood transfusions or blood products. Other alternatives, such as hemoglobin-based oxygen carriers and perfluorocarbons, are also being explored.

Topics: Blood Substitutes; Critical Care; Critical Illness; Erythropoietin; Female; Hemorrhage; Humans; Jehovah's Witnesses; Male; Middle Aged; Recombinant Proteins

Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. However, in Japan, only iron supplementation and blood transfusion were available for the treatment of anemia with cancer. On the other hand, in Europe and America, erythropoietic agents such as erythropoietin and novel erythropoiesis stimulating protein (NESP) have been clinically used for anemia in patients with cancer.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Hemolysis; Hemorrhage; Humans; Iron Metabolism Disorders; Neoplasms; Prognosis; Recombinant Proteins

Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.

Topics: Deamino Arginine Vasopressin; Erythropoietin; Estrogens, Conjugated (USP); Evidence-Based Medicine; Factor VIII; Fibrinogen; Hemorrhage; Humans; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency; Uremia; von Willebrand Factor

Anemia is common among patients with coronary artery disease (CAD) and portends a higher risk of short- and long-term mortality, major adverse cardiac events, and bleeding complications. Blood transfusion has long been the cornerstone of therapy for anemia; however, its benefit in patients with CAD is controversial and the appropriate threshold for transfusion has been widely debated. In this review, we summarize the studies evaluating the impact of anemia in patients with CAD undergoing percutaneous coronary intervention and address several issues regarding the use of transfusion in anemic patients. In addition, we discuss alternative options for the management of anemia, such as the use of erythropoietin, aqueous oxygen, and hemoglobin-based oxygen carriers.

Topics: Anemia; Angioplasty, Balloon, Coronary; Blood Substitutes; Blood Transfusion; Coronary Disease; Erythropoietin; Fibrinolytic Agents; Fluorocarbons; Hematinics; Hemoglobins; Hemorrhage; Humans; Oxygen; Recombinant Proteins; Risk Factors

The correction of anemia in dialysis patients with erythropoietin (EPO) can be frustrated by insufficient iron. To address this effect, we preloaded candidate EPO patients with intravenous iron in the early 1990s. Preloading with 900-1,525 mg of iron yielded the following results: 70% of patients had increasing hematocrits (HCTs) without EPO, and 40% of patients had HCTs greater than 30%. Apparent lack of iron led to blood loss studies. Routes evaluated were blood sampling, dialyzer clotting, blood in the dialyzer circuit and postdialysis bleeding. Projected annual losses were between 2,516 and 5,126 ml, depending on circuit and posttreatment losses. In terms of red cell loss, the results are comparable to those in the early days of dialysis before the introduction of current technology. Extension of these studies to daily dialysis predicts possible losses with this 6 times a week therapy of between 4,663 and 9,884 ml per year.

Topics: Anemia, Iron-Deficiency; Blood Coagulation; Catheters, Indwelling; Erythropoiesis; Erythropoietin; Hemorrhage; Humans; Infusions, Intravenous; Iron; Iron-Dextran Complex; Kidney Failure, Chronic; Models, Biological; Premedication; Recombinant Proteins; Renal Dialysis

Pharmacological approaches to reduce blood transfusion include the protease inhibitor aprotinin, lysine-analogue antifibrinolytics synthetic arginine-vasopressin derivatives (DDAVP) and recombinant factor VII (rfVIIa). These agents are known to prevent the need for blood after major surgery (cardiac, hepatic, and orthopaedic). Among the nonhemostatic agents erythropoietin (EPO) may be effective to reduce blood requirements in medical and surgical patients. Aprotinin is consistently effective in reducing blood transfusion in cardiac and hepatic surgical procedures, but there is little data to support its use in elective orthopaedic surgery. Antifibrinolytics show no evidence of efficacy in cardiac and hepatic surgery and its use is not warranted in orthopaedic surgery. Limited data suggest that DDAVP may be effective when a defect in platelet function is demonstrated. rFVIIa emerges as a promising haemostatic agent with proven benefit to reduce bleeding in haemophiliacs with inhibitors but might also be effective in patients with thrombocytopenia and thrombopathy, as well as in life-threatening hemorrhage in postsurgical patients. Ongoing studies will established its role a possible "universal haemostatic agent". Hematopoietic cytokines, such as EPO, may have a place to avoid blood transfusion in a variety of clinical conditions, including cancer and critically ill patients.

Topics: Antifibrinolytic Agents; Aprotinin; Blood Loss, Surgical; Blood Transfusion; Deamino Arginine Vasopressin; Erythropoietin; Factor VIIa; Hematologic Diseases; Hemorrhage; Hemostatics; Humans

The formation of red blood cells (RBCs) in the bone marrow is regulated by erythropoietin in response to a cascade of events. Anemia in the intensive care unit can be caused by a host of factors. Patients in the intensive care unit may have decreased RBC production and a blunted response to erythropoietin. Administration of recombinant human erythropoietin may stimulate erythropoiesis, increase hematocrit levels and hemoglobin concentration, and reduce the need for RBC transfusions.

Topics: Anemia; Anemia, Iron-Deficiency; Blood Specimen Collection; Bone Marrow Cells; Comorbidity; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Hemorrhage; Humans; Incidence; Intensive Care Units; Vitamin B 12 Deficiency

In spite of recent advances in the treatment of myelodysplastic syndromes (MDS), supportive care remains a very important part of the therapy. Red blood cells transfusions are the most important component of this supportive care. They transiently relieve anemia symptoms and alleviate their effects on quality of life and daily functioning. Platelet transfusion therapy is less frequently needed, at least in low-risk MDS. Dealing with an increased risk of infections linked to neutropenia, mainly by broad spectrum antibiotics, is also needed, more often in advanced stages of [dict: MDS] or when the MDS evolves to acute myeloid leukemia. Chronic red blood cell transfusions expose patients to various side-effects, including blood components intolerance reactions and alloimmunization risks, but also increased frequency of iron overload, a more significant problem in low-risk heavily transfused MDS patients, who have prolonged life expectancy. The use of growth factors is becoming a more and more important part of current supportive care. High-dose erythropoietin is able to reduce or suppress red blood cell transfusions needs in selected subgroups of MDS. The short-term use of granulocyte colony-stimulating factor is also often proposed in infections, although not formally established by prospective trials. Although trials of growth factors with thrombopoeitic activity have been performed with interleukin 11 and are underway with thrombopoeitin, none of them are available for routine use.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Growth Substances; Hemorrhage; Humans; Myelodysplastic Syndromes; Neutropenia; Recombinant Proteins; Thrombocytopenia

Topics: Blood Specimen Collection; Blood Substitutes; Blood Transfusion; Critical Care; Epoetin Alfa; Erythropoietin; Hematinics; Hemorrhage; Hemostatics; Humans; Jehovah's Witnesses; Monitoring, Physiologic; Nurse's Role; Nursing Assessment; Oxygen Consumption; Recombinant Proteins; Risk Factors; Transfusion Reaction; Treatment Refusal

Reduction in red blood cell mass, as well as structural and functional alterations of erythrocytes, occurs in critical illness. This review discusses these changes in red blood cell physiology, emphasizing the pathogenesis of anemia in intensive care unit patients.. Studies published in biomedical journals.. Anemia in intensive care unit patients resembles the anemia of chronic disease, being characterized by diminished erythropoietin production relative to decreased hematocrit, altered iron metabolism, and impaired proliferation and differentiation of erythroid progenitors in the bone marrow. Inflammatory mediators play a major role in the development of insufficient erythropoiesis and altered iron metabolism. Furthermore, a proinflammatory milieu promotes structural and functional alterations of erythrocytes, impairing their deformability and possibly impairing microvascular perfusion. Collectively, these changes in red blood cell physiology can impair oxygen transport to tissues and, thereby, might contribute to the development of multiple organ failure in critical illness.

Topics: Anemia; Critical Care; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Occult Blood; Phlebotomy

Anemia in the critically ill patient population is common. This anemia of critical illness is a distinct clinical entity characterized by blunted erythropoietin production and abnormalities in iron metabolism identical to what is commonly referred to as the anemia of chronic disease.. As a result of this anemia, critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units receive at least one red blood cell unit, and the average is close to five red blood cell units during their intensive care unit stay. There is little evidence that "routine" transfusion of stored allogeneic red blood cells is beneficial for critically ill patients. Most critically ill patients can tolerate hemoglobin levels as low as 7 mg/dL, so a more conservative approach to red blood cell transfusion is warranted.. Practice strategies should be directed toward a reduction of blood loss (phlebotomy) and a decrease in the transfusion threshold in critically ill patients.

Topics: Anemia; Critical Care; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Iron; Outcome and Process Assessment, Health Care; Phlebotomy

Topics: Anemia; Animals; Arginine; Bleeding Time; Blood Platelets; Endothelium, Vascular; Enzyme Inhibitors; Erythropoietin; Guanidines; Hemorrhage; History, 18th Century; History, 20th Century; Humans; Isoenzymes; Kidney Failure, Chronic; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Succinates; Uremia

Anemia and bleeding are commonly observed in patients with multiple myeloma (MM). Anemia in MM is multifactorial in origin. Three common causes are marrow replacement by the malignant cells, thereby reducing the available number of BFU-E, chronic renal failure and shortening of the half life of erythrocytes. Some patients with anemia but without renal failure show a good response to erythropoietin (Epo) with full correction of anemia. This indicates that human Epo is a promising therapeutic tool or treating myeloma-associated anemia. The incidence of severe bleeding complications is low, despite the diversity of abnormal hemostatic tests in patients with MM. These patients frequently show abnormal coagulation tests, including thrombin time, fibrin degeneration products, platelet aggregation tests and bleeding time. The most effective therapeutic approach to bleeding is to treat the underlying malignancy. Supplemental to this, plasma exchange is useful.

Topics: Anemia; Erythropoietin; Hemorrhage; Humans; Multiple Myeloma

Topics: Anemia; Aspirin; Bleeding Time; Blood Platelets; Blood Transfusion; Cryoprotective Agents; Deamino Arginine Vasopressin; Erythrocyte Transfusion; Erythropoietin; Estrogens; Hemorrhage; Humans; Parathyroid Hormone; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2; Uremia; von Willebrand Factor

Topics: Anemia; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Folic Acid; Hemoglobins; Hemorrhage; Hemostasis; Humans; Hypersplenism; Iron; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Uremia; Vitamin B 12

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Kidney Failure, Chronic

PTH may participate in the genesis of the anemia of uremia through at least three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing fibrosis of bone marrow cavity. A possible fourth mechanism through which PTH may contribute to the anemia of uremia is its effect on platelets. PTH inhibits platelet aggregation [53] and, as such, may play an important role in the genesis of the bleeding tendencies and the consequent blood loss in uremia.

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Colony-Forming Units Assay; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hematopoietic Stem Cells; Hemolysis; Hemorrhage; Humans; Hyperparathyroidism, Secondary; In Vitro Techniques; Mice; Parathyroid Hormone; Uremia

Uremia interferes with erythropoiesis, granulocyte, platelet, and immune functions. As a result, uremic patients are almost invariably anemic, and have a high incidence of infections and hemorrhagic complications. The anemia of renal failure, which is caused primarily by damage to the site of erythropoietin production is often complex, and complicated by hemolysis from a variety of mechanisms, iron deficiency, and so forth. Although hemodialysis ameliorates some of the hematologic complications to a variable degree, they remain a serious hinderance to the well being of this group of patients. Progress in understanding the mechanism of these problems and their therapy has been reviewed here.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Renal Dialysis; Testosterone; Testosterone Congeners

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Volume; Child; Deficiency Diseases; Erythropoietin; Hemorrhage; Hookworm Infections; Humans; Iron; Iron Deficiencies; Megakaryocytes; Thrombocytopenia; Thrombocytosis

Topics: Anemia, Hemolytic; Anemia, Neonatal; Bilirubin; Birth Weight; Blood Group Antigens; Diet; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Gestational Age; Hemoglobinometry; Hemorrhage; Humans; Immunization; Infant; Infant, Newborn; Isoantigens; Kinetics; Rh-Hr Blood-Group System; Thalassemia; Vitamin E Deficiency

Topics: Anemia; Animals; Bone Marrow; Dogs; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoiesis; Hemorrhage; Humans; Hypoxia; Iron Isotopes; Kidney; Kidney Diseases; Mice; Placenta; Polycythemia Vera; Rabbits; Rats; Stimulation, Chemical

Topics: Algorithms; Epoetin Alfa; Erythropoietin; Hematinics; Hemorrhage; Humans; Intraoperative Complications; Liver Diseases; Pancreatic Diseases; Recombinant Proteins

Autologous stem-cell transplantation has been shown to be a curative procedure for a variety of leukemias and lymphomas. Most transplants require RBC and platelet support. We report the ability to perform autologous transplantation without blood-product support.. In this study, we treated 26 patients with religious objection to blood products with autologous stem-cell support without the use of any blood products. Patients received a combination of granulocyte colony-stimulating factor (G-CSF), erythropoietin, and interleukin-11 or G-CSF alone to mobilize stem cells. Post-transplant patients received intravenous iron, erythropoietin, G-CSF, and epsilon aminocaproic acid.. There were two major bleeding complications (8%), with two treatment-related deaths (8%). There were three minor bleeding complications (12%). The median fall in hemoglobin level was 4.7 g/dL; the median hemoglobin level 30 days after transplantation was 9.2 g/dL. The median total number of days with platelet count less than 10 x 10(9)/L was 4 days; the median days to platelet recovery greater than 20 x 10(9)/L was 12 days.. Autologous stem-cell transplantation can be performed safely without the use of any blood products.

Topics: Adult; Combined Modality Therapy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemorrhage; Humans; Interleukin-11; Jehovah's Witnesses; Leukocyte Count; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Peripheral Blood Stem Cell Transplantation; Platelet Count; Survival Rate; Transplantation, Autologous

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Renal Dialysis; Safety; Thrombosis; Treatment Outcome

A number of animal studies and our own clinical trials point towards a possible influence of the renin-angiotensin-system (RAS) on erythropoietin (EPO) production. In this study we investigated the role of angiotensin II in the regulation of EPO production in humans.. After a hemorrhage of 750 ml as a basic physiological stimulus 72 healthy male volunteers received in a parallel design either placebo (physiologic electrolyte solution) for 6 h, angiotensin II i.v. for 6 h (1-3 microgram min-1, sufficient to increase systolic blood pressure by 20 mmHg), the selective AT1-receptor antagonist losartan, the ACE-inhibitor captopril, angiotensin II + losartan, or angiotensin II + captopril.. Administration of angiotensin II alone and in combination with captopril resulted in a significantly higher Cmax EPO (67% higher vs. placebo, P < 0.05) and AUCEPO (0-24h) (40% higher vs. placebo, P < 0.05). In the groups receiving losartan or captopril alone or the combination of angiotensin II + losartan no significant difference of Cmax EPO and AUCEPO(0-24h) compared to placebo could be detected.. This study shows in a model of controlled, basic physiological stimulation of renal EPO production that angiotensin II is able to increase EPO levels in humans. This effect of angiotensin II can be blocked by the specific AT1-receptor antagonist losartan but not by the ACE-inhibitor captopril. The result may be interpreted as a hint that one signal for the control of EPO production in humans may be mediated by angiotensin II (AT1)-receptors.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Erythropoietin; Heart Rate; Hematocrit; Hemoglobins; Hemorrhage; Humans; Infusions, Intravenous; Losartan; Male; Phlebotomy; Placebos

1. This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750 ml. 2. Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5 mg kg-1 over 20 min, followed by 0.5 mg kg-1 min-1), dipyridamole (0.21 mg kg-1 h-1) or placebo (0.9% NaCl) for 6 h following the phlebotomy. EPO concentrations were followed up to 72 h after phlebotomy. 3. Following blood loss EPO concentrations increased during all treatments. The AUCEPO (0,72 h) were not statistically significantly different (theophylline: 398 +/- 30, dipyridamole: 301 +/- 15, placebo: 332 +/- 57 [mu ml-1 h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activity was significantly increased during theophylline infusion. 4. In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.

Topics: Adenosine; Adult; Area Under Curve; Cardiovascular Agents; Creatinine; Dipyridamole; Erythropoietin; Hematocrit; Hemoglobins; Hemorrhage; Humans; Male; Phlebotomy; Phosphodiesterase Inhibitors; Single-Blind Method; Theophylline

Treatment of the anaemia of renal disease with recombinant human erythropoietin results in an improvement of haemostasis and an increased risk of thrombovascular accidents. In this prospective, placebo-controlled, double-blind, and cross-over study, the effects of low-dose acetylsalicylic acid (30 mg daily) on thrombotic and bleeding events during the initial period of treatment with erythropoietin in anaemic haemodialysis patients without previous thrombovascular accidents or known increased risk for thrombosis were investigated. During correction of the haematocrit and the first 3 months thereafter, group A (n = 68) received placebo and group B (n = 69) 30 mg acetylsalicylic acid daily. Cross-over took place after the 3rd month of a stable haematocrit. The study ended 3 months later. Target haematocrit (30-35%) was reached in 12.4 +/- 8 weeks (M +/- SD). In group A the bleeding time was 382 +/- 285 s, decreasing to 282 +/- 208 before cross-over (P < 0.01), and increasing to 395 +/- 271 (P < 0.05) thereafter. In group B the bleeding time was 390 +/- 381 s, 406 +/- 267 (NS), and 285 +/- 238 (P < 0.05) respectively. Twenty-two thrombovascular accidents were seen (16%, 13 during acetylsalicylic acid and 9 during placebo, NS), including 17 fistula thromboses. The incidence of bleeding events was not significantly different between regimens. In conclusion, erythropoietin treatment resulted in a reduction of the bleeding time. When 30 mg acetylsalicylic acid was taken during the treatment, the bleeding time did not decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Aspirin; Cross-Over Studies; Double-Blind Method; Erythropoietin; Female; Hematocrit; Hemorrhage; Humans; Kidney Failure, Chronic; Male; Platelet Count; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thrombosis

Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Erythropoietin; Female; Hemorrhage; Humans; Janus Kinase 2; Lung Diseases; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Pulmonary Alveoli; RAW 264.7 Cells; Receptors, Erythropoietin; Signal Transduction; STAT3 Transcription Factor; Terpenes

Protein "AND-gate" systems, in which a ligand acts only on cells with two different receptors, direct signaling activity to a particular cell type and avoid action on other cells. In a bifunctional AND-gate protein, the molecular geometry of the protein domains is crucial. Here we constructed a tissue-targeted erythropoietin (EPO) that stimulates red blood cell (RBC) production without triggering thrombosis. The EPO was directed to RBC precursors and mature RBCs by fusion to an anti-glycophorin A antibody V region. Many such constructs activated EPO receptors

Topics: Animals; Cell Communication; Cell Line; Darbepoetin alfa; Epitopes; Erythrocytes; Erythropoietin; Glycophorins; Hemorrhage; Humans; Ligands; Mice; Mice, Transgenic; Mutagenesis, Site-Directed; Protein Engineering; Recombinant Fusion Proteins; Single-Chain Antibodies

This study aimed to characterize the pathophysiology, including possible correlations, of clock gene expression and erythropoietin (EPO) production in the acute stage of blood hemorrhage. Specimens of human cortical tissues (right and left kidneys) and cardiac blood were collected at autopsy from 52 cases following mortality due to acute-stage blood hemorrhage following sharp instrument injury. BMAL1 and PER2 mRNA levels were determined by reverse transcription-polymerase chain reaction; BMAL1 and PER2 protein levels were assessed using immunohistochemistry; BMAL1 protein levels were quantitatively measured by western blotting; and serum EPO levels were measured by chemiluminescent enzyme immunoassay. Separately, a rat model of hemorrhagic conditions was generated and used to confirm the results obtained with autopsy-derived specimens. A positive correlation was observed between BMAL1 protein and serum EPO levels, but not between BMAL1 mRNA levels and serum EPO levels. We also noted that Per2 mRNA expression became elevated in humans who survived for > 3 h after acute hemorrhagic events, with subsequent decreases in serum EPO levels. The rat model showed that even short (30-min) intervals of blood loss yielded increases in both Bmal1 mRNA and serum EPO levels; longer (60-min) intervals resulted in increases in Per2 mRNA expression along with decreases in serum EPO. Thus, the acute-stage human hemorrhage cases and the rat hemorrhage model yielded similar tendencies for clock gene expression and EPO secretion. In conclusion, our results indicated that clock genes are involved in the regulation of EPO production during the early stages of hypoxia/ischemia resulting from the acute hemorrhagic events.

Topics: Acute Disease; Animals; ARNTL Transcription Factors; Disease Models, Animal; Erythropoietin; Gene Expression; Hemorrhage; Humans; Male; Period Circadian Proteins; Postmortem Changes; Rats, Sprague-Dawley; RNA, Messenger; Shock, Hemorrhagic; Time Factors

This study was designed to investigate the protective effects of centrally administered erythropoietin (EPO) on brain oxidative stress and inflammatory markers to protect the kidneys during hemorrhagic shock (HS).. Animals were assigned into three groups (n=6). Sham rats were subjected to cannulation of femoral artery and vein as well as stereotaxic surgery. In HS group, 50% of total blood volume was withdrawn and resuscitation was started 2h later. In EPO group, stereotaxic surgery in lateral ventricle was performed one week before induction of HS for administration of EPO (2IU) just before resuscitation. Plasma samples, kidney and brain tissues were allocated after a further 3h in all animals.. There was a significant increase in survival rate in the EPO group (69.3%) compared to the HS group (35.7%). Brain EPO administration significantly attenuated the rises in BUN, plasma Cr and NGAL, brain and renal MDA content and also increased SOD activity in the kidney and brain compared to the HS group. Brain, plasma and kidney TNF-α and IL-6 levels were significantly reduced by EPO compared to HS group. EPO increased the phosphorylation of Akt on Ser473 and eNOS mRNA expression in the kidney tissue compared to the HS group.. In conclusion, centrally administered EPO reduced pro-inflammatory and oxidative stress indices in the kidney and reduced apoptosis by activation of the Akt/eNOS signaling pathway. Hence, it can be hypothesized that EPO may play a major role in the central regulation of renal system as a neuromodulator.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Erythropoietin; Hemorrhage; Kidney; Male; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Shock, Hemorrhagic; Signal Transduction

Management of major haemorrhage as a result of trauma is particularly challenging when blood is not an option (BNAO). Evidence on therapeutic strategies in this situation is limited. The aim of this study was to evaluate the management and outcomes of patients who identified themselves as Jehovah's Witnesses (who usually refuse blood products) with traumatic haemorrhage at an Australian major trauma centre.. A retrospective review of patients from The Alfred Trauma Registry was conducted, including patients who were Jehovah's Witnesses presenting between January 2010 and January 2017. We examined demographics, injury characteristics, clinical progress, therapeutic interventions and outcomes at hospital discharge.. There were 34 patients meeting inclusion criteria, with 50% suffering major trauma. Anaemia was a clinical problem for 13 (38·2%) patients, with haemoglobin levels reaching a nadir of 69·7 g/l (95% CI: 56·7-82·7) on average 5·1 days (95% CI: 2·5-7·7) post admission. Various strategies were employed to reduce blood loss including six (46·2%) patients receiving tranexamic acid, nine (29·2%) patients receiving oral or intravenous iron and five (38·5%) receiving erythropoietin. Three patients received packed red cells, and two patients received synthetic haemoglobin-based oxygen carriers.. Numerous therapeutic strategies were employed inconsistently in this unique population of patients. Augmenting circulatory volume with an oxygen carrier acceptable to JW patients presents a novel approach to be considered in adjunct to other strategies. An international resource centre would assist clinicians faced with anaemia and BNAO.

Topics: Anemia; Australia; Blood Transfusion; Erythropoietin; Female; Hemorrhage; Humans; Jehovah's Witnesses; Male; Middle Aged; Tranexamic Acid; Treatment Refusal

Patient blood management aims to improve patient outcome and safety by reducing the number of unnecessary red blood cell transfusions and vitalizing patient-specific anemia reserves. While this is increasingly recognized as best clinical practice in elective surgery, the implementation in the setting of trauma is restrained because of typically nonelective (emergency) surgery and, in specific circumstances, allogeneic blood transfusions as life-saving therapy.. Viscoelastic diagnostics allow a precise identification of trauma-induced coagulopathy. A coagulation factor concentrate-based therapy is increasingly recognized as a fast and effective concept to correct coagulopathy and minimize blood loss. Using smaller tubes has a great potential to reduce the severity of phlebotomy-induced anemia. Washed cell salvage may reduce the number of allogeneic blood transfusions. Intravenous iron (with or without erythropoietin) may result in an increase of hemoglobin levels and reduced red blood cell transfusion requirements. Although a restrictive transfusion strategy is recommended in general, a target hemoglobin level of 7-9 g/dl is recommended in acute bleeding patients.. In the setting of trauma, options to avoid unnecessary blood loss and reduce blood transfusion are manifold. These are likely to improve safety and outcome of trauma patients while potentially reducing therapeutic costs.

Topics: Anemia; Blood Coagulation Disorders; Blood Loss, Surgical; Blood Transfusion; Erythropoietin; Hemorrhage; Humans; Monitoring, Physiologic; Operative Blood Salvage; Treatment Outcome; Wounds and Injuries

The leading role in the regulation of erythropoietic activity of adherent bone marrow cells under conditions of post-hemorrhagic anemia is played by classical MAP kinase pathway (ERK pathway). Erythropoietin is not the decisive factor in the formation of erythropoietic activity of adherent cells. PI3K, MAPK/ERK 1/2, and p38-signaling proteins are not the main regulators of local production of erythropoietin after 30% loss of circulating blood volume.

Topics: Anemia; Animals; Bone Marrow Cells; Chromones; Disease Models, Animal; Erythropoiesis; Erythropoietin; Flavonoids; Gene Expression Regulation; Hemorrhage; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Morpholines; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridines; Signal Transduction

Epidermolysis bullosa (EB) is comprised of a group of hereditary mechanobullous disorders that are characterised by extremely fragile skin and mucous membranes. This results in blister formation and non-healing wounds. This case report describes the results of an innovative treatment of two large skin lesions in a newborn with dystrophic recessive EB (DEB) who experienced bacterial superinfections and progressive anaemisation. The lesions were treated with platelet gels derived from allogeneic cord blood (cord blood platelet gel, CBPGs). The skin lesions were clinically evaluated and treated with CBPG weekly until they completely healed. The first and second lesion required CBPG applications for 2 and 4 weeks, respectively. Both lesions were monitored weekly for 6 weeks after the last CBPG application, and no significant relapses were observed during the follow-up period. This case indicates that CBPG is an effective and safe therapeutic option for managing newborns with DEB, particularly as treatment and prevention of fluid loss and superinfection.

Topics: Anemia; Anti-Bacterial Agents; Bacterial Infections; Blood Platelets; Epidermolysis Bullosa Dystrophica; Erythropoietin; Female; Fetal Blood; Gels; Hemorrhage; Humans; Infant, Newborn; Superinfection

In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues.

Topics: Anemia; Antifibrinolytic Agents; Aprotinin; Blood Coagulation Factors; Blood Transfusion; Clinical Trials as Topic; Critical Illness; Crystalloid Solutions; Erythropoietin; Hematinics; Hemorrhage; Humans; Hydroxyethyl Starch Derivatives; Iron; Isotonic Solutions; Meta-Analysis as Topic; Observational Studies as Topic; Plasma Substitutes; Recombinant Proteins; Tranexamic Acid; Transfusion Reaction

Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1β, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Caspase 3; Cytokines; Disease-Free Survival; Erythropoietin; Hematopoiesis; Hemorrhage; Inflammation; Kidney; Lethal Dose 50; Leukopenia; Male; Mice; MicroRNAs; NF-kappa B; Radiation Injuries; Thrombocytopenia; Water

Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in Hbb(th3/+) mice with thalassemia intermedia, where it contributes to the suppression of hepcidin and the systemic iron overload characteristic of this disease.

Topics: Anemia; Animals; beta-Thalassemia; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gene Expression Profiling; Hemoglobins; Hemorrhage; Hepcidins; Hormones; Iron; Iron Overload; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The aim of this retrospective cohort study was to identify early risk factors of mortality and develop a mortality risk stratification instrument for severely anaemic Jehovah's Witness patients. It has been shown that Jehovah's Witness patients with the Auckland Anaemia Mortality Risk Score (Auckland AMRS) of 0 to 3 had 4% mortality, Auckland AMRS 4 to 5 32%, Auckland AMRS 6 to 7 50% and Auckland AMRS 8 and above 83%. It is concluded that the Auckland AMRS predicts mortality of severely anaemic Jehovah's Witness patients.

Topics: Adolescent; Adult; Aged; Anemia; Cardiovascular Diseases; Erythropoietin; Factor VIIa; Female; Filgrastim; Folic Acid; Granulocyte Colony-Stimulating Factor; Hemorrhage; Hospital Mortality; Hospitals, Public; Humans; Infections; Iron; Jehovah's Witnesses; Kidney Failure, Chronic; Male; Middle Aged; New Zealand; Plasma; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Vitamin B 12; Young Adult

In cases with severe anemia and significant hemorrhages, intensive care of a person refusing blood products is challenging. Owing to ethical aspects associated with conviction, treatment is easily subject to prejudice. Research data on this particular topic are insufficient, thus, treatment decisions are based on case reports. Treatment modalities that can be approved by the patients should be scrutinized as early as possible and individuality taken into consideration. Epoetin, iron and vitamins are readily started. Attempts have to be made to guarantee adequate blood volume, oxygen transport and hemostasis. Mechanical ventilation, high fraction of inspired oxygen and sedation are utilized as supportive treatments, when severe anemia is improving.

Topics: Anemia; Blood Transfusion; Conscious Sedation; Critical Care; Erythropoietin; Hemorrhage; Humans; Iron; Recombinant Proteins; Respiration, Artificial; Treatment Refusal; Vitamins

Revision total hip arthroplasty (THA) is associated with greater blood loss than primary THA. Jehovah's Witnesses will not accept transfusions of blood or blood products and are thus at an increased risk for complications due to perioperative anemia. The purpose of this study was to report the clinical outcomes, radiographic outcomes, morbidity, and mortality of Jehovah's Witnesses who were medically optimized and underwent revision THA. Databases from 2 institutions were reviewed to identify 10 patients (11 THAs) who were Jehovah's Witnesses undergoing revision THA with a minimum 24-month follow-up. At most recent follow-up, all patients were doing well clinically, with Harris Hip Scores greater than 80 points. Radiographic evaluation demonstrated well-positioned components and no progressive radioluciencies. No major perioperative medical or surgical complications occurred in patients undergoing THA. Revision THA for aseptic causes results in good clinical outcomes in patients who are preoperatively optimized before undergoing surgery.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthroplasty, Replacement, Hip; Blood Transfusion; Erythropoietin; Female; Hemorrhage; Hip Joint; Humans; Jehovah's Witnesses; Male; Middle Aged; Osteolysis; Prosthesis Failure; Prosthesis-Related Infections; Reoperation

Adult rats are generally not considered as a suitable model for the peripheral blood micronucleus (PBMN) assay in regulatory consideration, owing to the splenic removal of the micronucleated cells from circulation. Although prior bleeding (PrB) increases the sensitivity of the PBMN assay in young rats, the volume of bleeding and the associated stress caused are major concerns for its possible use in genotoxicity studies. The present study was aimed to overcome these limitations in using pre-bled young rats in genotoxicity studies. The bleeding volume was reduced by the simultaneous use of erythropoietin (EPO) to increase the sensitivity of PBMN assay. Young Sprague-Dawley (SD, 26 days) rats were used in the study. The kinetics of RETs-to-ERTs ratio was determined in response to EPO (10-3000 IU/kg) or PrB (0.1-1.0 ml) at different time points (0, 6, 12, 24, 36, 48, 72 and 96 h). Injection of EPO (30 IU/kg) and PrB (0.5 ml) led to a significant increase in the MN frequency in the PBMN assay in response to cyclophosphamide and zidovudine. The effect of EPO treatment and/or PrB on cell viability and proliferation in the bone marrow (BM) was examined. The results of the present study clearly demonstrate that the simultaneous use of both EPO and PrB enhances the sensitivity of the PBMN assay in young rats due to increased cellular proliferation in the BM. This may provide a useful experimental model for the evaluation of marginally active genotoxicants.

Topics: Animals; Bone Marrow Cells; Cell Proliferation; Cyclophosphamide; DNA Damage; Erythropoietin; Hemorrhage; Kinetics; Male; Micronucleus Tests; Mutagens; Rats; Rats, Sprague-Dawley; Reticulocytes; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Zidovudine

Hemorrhage is frequently seen during the early phases of polytrauma management and intensive care treatment of the severely injured. Traumatic coagulopathy as well as the sometimes overlooked hyperfibrinolysis may lead to further complications. Therefore, transfusion of blood products and coagulation factors is often crucial. Jehova's Witnesses reject transfusions of blood and blood products due to religious convictions. In this case report a therapeutic approach of a multiple trauma patient suffering from traumatic brain injury, blunt chest trauma and liver laceration is described, who has been treated without blood products. As one main focus, ethical as well as legal aspects are discussed. Beside therapeutic concepts, such as the administration of coagulation factors, recombinant erythropoietin and iron, ethical and legal aspects remain part of the controversial discussion.

Topics: Algorithms; Blood Coagulation Factors; Blood Transfusion; Brain Injuries; Contraindications; Contusions; Critical Care; Erythropoietin; Female; Hemorrhage; Hemostatic Techniques; Humans; Jehovah's Witnesses; Liver; Lung Injury; Multiple Trauma; Religion and Medicine; Rupture; Spleen; Tomography, X-Ray Computed; Trauma Centers; Ultrasonography; Young Adult

Circulating erythropoietin (EPO) is mainly derived from the kidneys, and the serum concentration is rapidly increased in response to anemia and hypoxia. The present study investigated postmortem serum EPO levels in injury death cases (n=185, postmortem time<48 h, survival time <7 days: sharp instrument injury, n=44 and blunt injury, n=141) with regard to survival time, compared with C-reactive protein (CRP) as a marker of inflammation. Serum levels of both markers were independent of postmortem time. A survival time-dependent increase in serum EPO up to about 100 mU/ml was seen within 6h of sharp instrument injury to the heart or a proximal major vessel (thoracic aorta or subclavian/carotid artery) and blunt injury with massive hemorrhages, showing high correlations (r=0.957 and r=0.822, respectively, P<0.0001), whereas the increase was insignificant (P>0.05) for sharp instrument injury to a peripheral vessel or lungs/abdominal viscera and blunt injury with minor hemorrhages over the same survival period. A further increase (>100 mU/ml) was often detected in cases of death about 24h after blunt injury, irrespective of the type of injury. In contrast, a gradual increase in serum CRP level was seen about 12-24h after blunt injury. These findings suggest that serum EPO can be a marker for investigating survival time within 6h of major injury involving acute massive hemorrhaging.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Case-Control Studies; Erythropoietin; Female; Forensic Pathology; Hemorrhage; Humans; Male; Middle Aged; Postmortem Changes; Survival Analysis; Wounds, Nonpenetrating; Wounds, Stab

Oxygen-carrying capacity of blood is reduced in anemic infants because of low hemoglobin levels. Red blood cell transfusions become necessary if low hematocrit causes tissue hypoxia. No reliable parameters exist for detecting chronic tissue hypoxia. Vascular endothelial growth factor is upregulated by hypoxia; hence, elevated vascular endothelial growth factor levels may be a marker for tissue hypoxia and may indicate the need for red blood cell transfusions.. In a prospective study, plasma vascular endothelial growth factor levels were measured in 3 groups of infants suspected of requiring red blood cell transfusions to find a vascular endothelial growth factor cutoff value indicative of tissue hypoxia. The 3 groups were acute anemic (an episode of acute bleeding [hematocrit drop > 5%] per day); chronic anemic (hematocrit drop < 5% per day); and nontransfused (hematocrit drop < 5% per day) but not meeting clinical criteria for a transfusion. Blood was sampled before transfusion and again 48 hours after transfusion if required. Plasma vascular endothelial growth factor and erythropoietin concentrations were measured.. Vascular endothelial growth factor concentrations were lower in acutely anemic compared with chronically anemic infants, whereas erythropoietin levels did not differ between these groups. The vascular endothelial growth factor concentration was <140 pg/mL in all acutely anemic infants, and this was deemed the threshold level indicating sufficient tissue oxygenation in subsequent analysis. We found that 30% of chronically anemic and 43% of nontransfused infants had vascular endothelial growth factor levels of >140 pg/mL. In transfused infants, with elevated vascular endothelial growth factor levels, red blood cell transfusion resulted in lowering of vascular endothelial growth factor concentrations.. Vascular endothelial growth factor concentrations of >140 pg/mL may indicate insufficient oxygen delivery to tissues and may serve as a marker of the need for transfusion or of tissue hypoxia in other diseases.

Topics: Anemia, Neonatal; Biomarkers; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hemorrhage; Humans; Hypoxia; Infant, Newborn; Infant, Premature, Diseases; Male; Predictive Value of Tests; Prospective Studies; Reference Values; Vascular Endothelial Growth Factor A

Evaluation of the clinical efficacy and tolerance of metronomic chemotherapy as salvage therapy in a young patient with advanced, platinum resistant, ovarian carcinoma and bad performance status.. We tried palliative chemotherapy with daily low dose oral cyclophosphamide with a patient suffering from stage IIIC ovarian cancer that responded to daily cyclophosphamide (CTX) after no response to chemotherapy with paclitaxel and carboplatin as first line and progression after second line with topotecan. The progression-free survival time on daily low dose oral cyclophosphamide treatment was 65 months without side effects. She was well during the chemotherapy and lived a normal working and social life.. We think that use of low dose of oral CTX should be investigated further as a strategy against tumour progression after standard chemotherapy in patients who are platinum resistant with poor performance status.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Colonic Neoplasms; Colostomy; Cyclophosphamide; Cystadenocarcinoma, Serous; Disease-Free Survival; Drug Administration Schedule; Drug Evaluation; Drug Resistance, Neoplasm; Epoetin Alfa; Erythropoietin; Fatal Outcome; Female; Follow-Up Studies; Hemorrhage; Humans; Intestinal Obstruction; Karnofsky Performance Status; Laparotomy; Ovarian Neoplasms; Ovariectomy; Paclitaxel; Palliative Care; Peritoneal Neoplasms; Recombinant Proteins; Salvage Therapy; Topotecan; Urinary Bladder Neoplasms; Vitamins

In contrast to other sympathetic outflow tracts, renal sympathetic nerve activity (RSNA) decreases in response to hypotensive hemorrhage. The functional significance of this "paradox" is not known. We tested the hypothesis that RSNA modulates renal perfusion and thus erythropoietin (EPO) release after transient hypotensive hemorrhage in anesthetized rats. Plasma EPO was measured before and after 30 min of transient hypotensive hemorrhage (i.e., -40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 min thereafter in sham-denervated rats, and after renal denervation (DNX) or bilateral cervical vagotomy (VX) to abolish/blunt the RSNA decrease mediated by a cardiopulmonary reflex. RSNA, renal Doppler flow, renal vascular resistance (RVR), resistance index, and oxygen delivery/uptake (Do(2)/Vo(2)) were measured. RSNA decreased in intact animals (-40 +/- 5% from baseline, P < 0.05). This was blunted by VX. With intact nerves, EPO level did not increase. In DNX rats, EPO was increased at minute 120 (49 +/- 3 vs. 74 +/- 2 mU/ml; P < 0.05), in VX rats this (47 +/- 2 vs. 62 +/- 4 mU/ml; P < 0.05) was less pronounced. Do(2) in DNX rats was lower compared with intact and VX rats (0.25 +/- 0.04 vs. 0.51 +/- 0.06 and 0.54 +/- 0.05 ml O(2)/min; P < 0.05) due to lower Doppler flow and increased RVR. RVR and Do(2) were similar in intact and VX rats, but resistance index differed between all groups (0.70 +/- 0.02 vs. 0.78 +/- 0.02 vs. 0.85 +/- 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. Vo(2) was unaffected by VX and DNX. Renal sympathoinhibition during hypotensive hemorrhage might help to preserve sufficient oxygenation of renal tissue by modulation of hemodynamic mechanisms that act to adapt renal oxygen availability to demand.

Topics: Animals; Blood Pressure; Erythropoietin; Hemorrhage; Hypotension; Kidney; Kidney Diseases; Lactic Acid; Male; Oxygen; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sympathetic Nervous System; Vascular Resistance

Hematopoietic stem cells (HSCs) divide and give rise to more committed progenitors, which ultimately produce all lineages of blood cells. HSCs can be induced to enter the cell cycle in vitro and in vivo by stimulatory cytokines and in vivo by ablation of bone marrow (BM) cells with irradiation or chemotherapeutic agents. Although it has been postulated that rates of HSC proliferation increase with normal hematopoietic stresses, such as infection or hemorrhage, this hypothesis has never been directly tested. The ability to analyze HSCs prospectively by cell-surface phenotype c-kit(+), Thy1.1(lo), Sca-1(+), Linage(neg/lo) has allowed us to perform a detailed examination of the effects of bleeding on the cell cycle kinetics of HSCs. Our results demonstrate for the first time that HSCs in both the BM and the spleen proliferate and self-renew in response to tail-vein bleeding in mice. This response was suppressed when red blood cells, but not when white blood cells, were transferred after bleeding. Thus, regulators of HSC proliferation can sense and respond to red blood cell levels.

Topics: Animals; Biomarkers; Blood Group Antigens; Bone Marrow Cells; Cell Count; Cell Proliferation; DNA; Erythrocytes; Erythropoietin; Flow Cytometry; G2 Phase; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Hemorrhage; Macrophage-1 Antigen; Mice; Mice, Inbred C57BL; Mitosis; S Phase; Spleen

Jehovah's Witness followers do not accept blood derived transfusions and available methods for avoiding transfusion have been used with degrees of success, demonstrating that the probability of death after trauma in these patients may not be significantly different from religious groups. In this report, we describe the case of a child victim of a multiple trauma with severe anemia due to blood loss, whose family would not authorize blood transfusion because of their Jehovah's Witness faith. We discuss the current indications for restricting transfusion, as well as highlighting new tools that contribute to the success of minimizing blood loss, thus avoiding transfusion.

Topics: Accidents, Traffic; Anemia; Anti-Bacterial Agents; Case Management; Child; Colloids; Combined Modality Therapy; Craniocerebral Trauma; Crystalloid Solutions; Culture; Debridement; Dopamine; Erythropoietin; Ferric Compounds; Fluid Therapy; Folic Acid; Hemorrhage; Humans; Isotonic Solutions; Jehovah's Witnesses; Male; Multiple Trauma; Plasma Substitutes; Vitamin K

Dysregulated erythropoietin (EPO) plasma levels may play a role in the pathophysiology of chronic liver disease (CLD) because chronic anaemia is frequently observed in patients with liver cirrhosis. We aimed to identify the factors contributing to EPO regulation in patients with CLD.. Plasma EPO concentrations were correlated with clinical and laboratory parameters in 111 CLD patients and 220 healthy controls.. Anaemia, though generally mild, was common in CLD patients, and thrombocytopenia and previous bleeding episodes were observed in two-thirds of the patients. Plasma EPO levels were significantly elevated in CLD patients (P < 0.001). EPO increased according to Child's stages of cirrhosis, independently of the aetiology of CLD. EPO correlated with haemoglobin (r= -0.498, P < 0.001). Additionally, EPO independently correlated with markers of liver dysfunction, e.g. prothrombin time, albumin concentration or cholinesterase activity, and platelet count. EPO was also significantly elevated in patients with a current bleeding tendency and with prior gastrointestinal haemorrhages. EPO levels were increased in patients with impaired pulmonary function, e.g. decreased diffusion capacity, vital capacity or hyperventilation. Interestingly, plasma interleukin-6 (IL-6) concentrations positively correlated with EPO (r=0.277, P = 0.003), suggesting a possible mechanism of EPO upregulation in patients with CLD through IL-6 dependent pathways, e.g. binding of STAT transcription factors in the putative EPO promoter region.. EPO is upregulated in patients with chronic liver diseases in response to anaemia, bleeding complications, impaired pulmonary function, thrombocytopenia and liver dysfunction. IL-6 dependent pathways could be involved in mediating elevated EPO levels in CLD patients.

Topics: Adolescent; Adult; Aged; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemorrhage; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Respiratory Function Tests; Severity of Illness Index; Thrombocytopenia; Up-Regulation

Topics: Aged; Anemia; Antibodies, Antineutrophil Cytoplasmic; Erythropoietin; Female; Hemorrhage; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lung Diseases; Pulmonary Alveoli; Renal Dialysis; Treatment Outcome

Topics: Anemia; Blood Substitutes; Emergency Medical Services; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Fluorocarbons; Hemorrhage; Humans; Infections; Recombinant Proteins; Resuscitation; Risk Factors

To study direct and indirect effects of EPO on haemostasis.. Experimental, randomised.. Forty-eight New Zealand rabbits.. Animals were anaesthetised, ventilated and monitored continuously for blood pressure, heart rate, body temperature, and carotid blood flow variations and were randomised into four groups: control, EPO bolus 2400 IU kg(-1), fractionated EPO (one injection a week of 600 IU kg(-1) for 4 weeks), homologous red blood cell transfusion to reach the Ht level of the fractionated EPO group. A compression injury and a 75% stenosis of the carotid artery triggered a series of cyclic flow reductions (CFRs). CFRs were observed for a 20 min period in each group. Ear immersion bleeding time (BT) and hepato-splenic bleeding were performed at the end of the experiment. Biology was performed at the end of the thrombosis period: blood cells count, Hte, activated partial thromboplastin time, fibrinogen, arachidonic-induced platelet aggregation, EPO dosages.. No significant increase in thrombosis (CFRs) in the two EPO groups and in the transfused group. Increase in Hte in the fractionated EPO group versus control. Group EPO bolus: decrease in BT and hepato-splenic bleeding versus control; decrease in hepato-splenic bleeding versus fractionated EPO group, increase in platelet aggregation velocity versus control.. EPO did not increase the thrombotic risk in this rabbit model. EPO bolus decreased BT and hepato-splenic bleeding.

Topics: Animals; Bleeding Time; Blood Pressure; Body Temperature; Carotid Arteries; Erythrocyte Transfusion; Erythropoietin; Fibrinogen; Heart Rate; Hemobilia; Hemorrhage; Partial Thromboplastin Time; Platelet Aggregation; Rabbits; Recombinant Proteins; Regional Blood Flow; Thrombosis

Despite the fact that pig fetuses in late gestation have extensive erythropoiesis, low blood pO(2) and low hemoglobin concentrations, piglets are born without detectable concentrations of plasma erythropoietin (Epo). In the present study, we have examined the hypothesis that long-term hypoxic stimuli are less efficient than short-term stimuli in stimulating Epo production in perinatal pigs. From fetuses collected by hysterectomy 5 days before term, new-born piglets and piglets 2 and 5 weeks old, blood in amounts corresponding to 2% of body weight was withdrawn from the jugular vein. Twenty-four hours later the animals were killed and their kidney and liver Epo mRNA analysed by a competitive RT-PCR assay. Plasma Epo concentration was estimated by a solid-phase, two-site sequential chemiluminescent enzyme immunometric assay. We found that in nearly fully developed fetuses and in new-born piglets, the concentration of Epo mRNA did not increase upon bleeding. This is in contrast to earlier findings in sheep. In 2- and 5-week-old piglets, bleeding was associated with a 12-15-fold increase in kidney Epo mRNA. In the 2- and 5-week-old piglets, bleeding evoked increased translation of Epo mRNA into the protein hormone. Also in new-born piglets, increased plasma levels of Epo accompanied bleeding, whereas significant changes in gene Epo expression were not observed.

Topics: Animals; Animals, Newborn; Erythropoiesis; Erythropoietin; Fetus; Gene Expression Regulation, Developmental; Hemoglobins; Hemorrhage; Kidney; Liver; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine

Topics: Adult; Anemia; Blood Substitutes; Christianity; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Multiple Trauma

Previous reports suggested that immature ovine fetuses have a greater erythropoietin response to hemorrhage than those near term. This study tested the hypothesis that immature ovine fetuses would expand their red cell mass more rapidly than near term fetuses after hemorrhage.. Chronically catheterized immature ovine fetuses at 109.5 +/- 0.3 (mean +/- SE) days' gestation (term = 150 days) were studied over a 10-day period. They either underwent hemorrhage of 40% of their measured blood volume on day 3 or were in a time control group monitored without hemorrhage. Red cell mass, hematocrit, blood volume, plasma volume, and plasma erythropoietin concentrations were measured at 24- and 48-hour intervals. Responses in the immature fetuses were compared with responses in near term fetuses.. In the control group red cell mass, hematocrit, blood, and plasma volumes increased significantly, whereas plasma erythropoietin concentration decreased significantly with advancing gestational age. In immature fetuses that underwent hemorrhage, the relative changes in red cell mass, hematocrit, and plasma erythropoietin concentration were not significantly different from those seen in the near term fetuses. The only significant posthemorrhage difference was that the increases in blood and plasma volumes were greater in the immature compared with the near term fetuses.. Immature and mature fetuses have similar erythrocyte and erythropoietin responses to moderately severe hemorrhage. The larger blood and plasma volume responses in the immature fetuses are consistent with the concept that they have a greater extracellular fluid volume.

Topics: Animals; Blood Volume; Erythrocyte Volume; Erythropoietin; Female; Fetal Blood; Fetal Diseases; Gestational Age; Hematocrit; Hemorrhage; Plasma Volume; Pregnancy; Sheep

Renal transplantation is the treatment of choice for many patients with end-stage renal disease. In the donor, renal excretory function is not affected after nephrectomy; however, little is known about other functions such as erythropoietin production. We studied the erythropoietin production in renal donors after nephrectomy.. We included healthy individuals fulfilling the criteria for kidney donation. Blood samples were collected before and monthly from 1 to 6 months after nephrectomy. Complete blood cell counts and erythropoietin were assayed.. Eight kidney donors were studied. A significant increase in erythropoietin levels was observed during the first 3 months, but no difference was observed by the 4th month as compared with basal values.. Erythropoietin production rose during the first 3 months after nephrectomy. However, erythropoietin was normal by the 4th month. Unchanged hemoglobin levels may suggest that the compensatory production of erythropoietin could participate in the preservation of an adequate physiological status of the donor after nephrectomy.

Topics: Adult; Erythropoietin; False Positive Reactions; Female; Follow-Up Studies; Hemoglobins; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Nephrectomy; Prospective Studies; Tissue Donors

Erythropoiesis occurs in the presence of erythropoietin (EPO) without macrophages in vitro. In hematopoietic tissues, however, erythroid cells associate closely with stromal macrophages, forming erythroblastic islands via interactions with adhesion molecules. To elucidate the role of macrophages in erythropoiesis, we selectively abrogated stromal macrophages of splenic red pulp of phlebotomized mice by injection with dichloromethylene diphosphonate encapsulated in multilamellar liposomes (CL2MDP-liposome). In the spleen, no erythropoietic activity occurred until 5 days after the treatment. Colony assay revealed that the erythropoiesis was suppressed at the level of CFU-E. The splenic erythropoietic activity gradually developed from day 6 after the treatment, when F4/80+ macrophages began to appear in the red pulp. EPO mRNA was expressed in kidney but not in liver or spleen of phlebotomized mice injected with CL2MDP-liposome, and the serum EPO concentration in these mice was higher than that in phlebotomized mice. These findings suggest that abrogation of stromal macrophages by injection with CL2MDP-liposome impairs the splenic microenvironment for erythropoiesis induced by hypoxic stress, and this may be an excellent experimental model for further characterization of the in vivo role of splenic macrophages in erythropoiesis.

Topics: Anemia; Animals; Clodronic Acid; Colony-Forming Units Assay; Depression, Chemical; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hemorrhage; Humans; Hypoxia; Kidney; Liposomes; Liver; Macrophages; Mice; Mice, Inbred BALB C; Phlebotomy; Recombinant Proteins; RNA, Messenger; Spleen; Stromal Cells

Orthopedic trauma is a major source of morbidity and mortality in the United States and other countries. Major orthopedic trauma often results in significant blood loss, which is the most common cause of shock in the trauma setting. Transfusion of allogeneic blood and blood products may be used to maintain blood pressure but may not be the most effective therapy for the acute anemia that results from trauma-induced hemorrhage. Because acute anemia can interfere with successful and timely rehabilitation of these patients, it is important to be aggressive in treating anemia. One approach is to administer Epoetin alfa to stimulate erythropoiesis. A pilot study is currently in progress to test the efficacy of this approach in major trauma patients.

Topics: Blood Transfusion; Blood Transfusion, Autologous; Epoetin Alfa; Erythropoietin; Fractures, Bone; Hematinics; Hemorrhage; Humans; Recombinant Proteins

To determine incidence, severity, characteristics, and causes of anemia and transfusion requirements in medical intensive care patients.. Open prospective clinical study in a 24-bed medical intensive care unit in a tertiary-care university hospital.. Patients (N = 96) treated in the intensive care unit for >3 days.. None.. Parameters of erythropoiesis and red blood cell metabolism, including hemoglobin, reticulocyte counts, serum iron, transferrin, ferritin, haptoglobin, vitamin B12, folic acid, and erythropoietin concentrations were determined serially. Diagnostic blood loss and red blood cell transfusions were recorded, and the total blood loss was estimated from changes in hemoglobin concentrations and the amount of hemoglobin transfused.. The median hemoglobin concentration was 12.1 g/dL at admission and 11.2 g/dL at the end of the intensive care unit stay. A total of 74 patients (77%) suffered from anemia and received 257 red blood cell units, approximately half of which were given within the first 5 days. Three patients who received 19 red blood cell units were admitted with acute gastrointestinal bleeding, but in the remainder, a median total blood loss of 128 mL/d was not (n = 60) or not solely (n = 11) a result of overt bleeding. Diagnostic blood loss declined from a median of 41 mL on day 1 to <20 mL after 3 wks and contributed 17% (median) to total blood loss. Acute renal failure, fatal outcome, and simplified acute physiology score >38 on admission were associated with a 5.8-, 7.0-, and 2.8-fold increase in total blood loss. Reticulocyte counts and erythropoietin concentrations were inappropriately low for the degree of anemia, and plasma transferrin saturation was mostly <20%.. Anemia is frequent and results in a high requirement for red blood cell transfusions in the medical intensive care setting. A major proportion of blood loss is not caused by overt bleeding or diagnostic blood sampling but, rather, may result from various other reasons, e.g., occult gastrointestinal bleeding and renal replacement therapy. The erythropoietic response to anemia is blunted, probably as a consequence of an inappropriate increase in erythropoietin production and diminished iron availability. (Crit Care Med 1999; 27:2630-2639)

Topics: Anemia; APACHE; Blood; Critical Care; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Hemorrhage; Hospitals, University; Humans; Intensive Care Units; Length of Stay; Logistic Models; Male; Middle Aged; Prospective Studies

Intravenous iron supplementation is often necessary in recombinant human erythropoietin (r-HuEPO)-treated haemodialysis (HD) patients, but rarely in r-HuEPO-treated peritoneal dialysis (PD) patients. This may be due to differences in iron absorption or blood loss.. Iron absorption (whole-body counting after ingestion of a radiolabelled iron test dose) and iron metabolism were compared in eight iron-replete rHuEPO-treated PD patients (serum ferritin 100-500 microg/l) and 68 healthy iron-replete controls (sufficient iron in bone marrow specimen).. Mucosal uptake (13.4+/-9.8%), mucosal transfer (0.34+/-0.18) and iron retention (4.9+/-4.0) in PD patients was significantly lower than in controls (42.9+/-18.8%, P < 0.0001, 0.63+/-0.18, P < 0.0001, and 28.0+/-16.7%, P<0.0001).. Iron absorption is impaired in PD patients, as we have shown previously for HD patients. One reason for higher iron needs in HD patients may be higher blood losses due to the dialysis procedure and blood sampling for laboratory tests.

Topics: Absorption; Adolescent; Adult; Anemia, Iron-Deficiency; Erythropoiesis; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hemorrhage; Humans; Infusions, Intravenous; Iron; Iron Compounds; Iron Deficiencies; Kidney Diseases; Male; Peritoneal Dialysis; Receptors, Transferrin; Recombinant Proteins

Topics: Antigens, CD; Blood Platelets; Cold Temperature; Erythropoietin; Estrogens; Fibrinogen; Hemorrhage; Humans; Injections, Intravenous; Integrin beta3; Integrins; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Renal Dialysis; Uremia; von Willebrand Factor

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.. 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.. 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).. 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.

Topics: Animals; Erythrocyte Volume; Erythropoietin; Fetal Diseases; Hemorrhage; Iron; Sheep

Administration of erythropoietin augmented the mitotic activity in the erythroid crown of erythroblastic islands in polycythemic as well as normal rats. The phenomenon seems to be due to activation of erythropoietic synthesis by the central macrophage in reconstructing erythroblastic islands.

Topics: Acute Disease; Anemia; Animals; Bone Marrow Cells; Cell Division; Erythroblasts; Erythropoiesis; Erythropoietin; Female; Hemorrhage; Mitosis; Polycythemia; Rats; Time Factors

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.. 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.. 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).. 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.

Topics: Animals; Blood Volume; Erythropoietin; Female; Fetal Blood; Fetus; Gestational Age; Hematocrit; Hemorrhage; Iron; Plasma Volume; Pregnancy; Reticulocyte Count; Sheep

Anemia is a cardinal feature of chronic renal failure (CRF) which contributes significantly to the clinical syndrome of chronic uremia. We have conducted a detailed examination of the hematological changes in CRF in the inbred mouse strain C57BL/6J. As in the human situation, CRF mice presented major hematological changes affecting primarily the erythroid cell series. Despite the presence of abundant iron stores in the bone marrow, the CRF mice developed a hypoproliferative anemia of a severity commensurate with the degree of renal impairment. The levels of circulating erythropoietin (EPO) in CRF mice were not significantly different from those in normal control littermates and were therefore inappropriately low for the degree of anemia. In contrast acutely bled control mice with normal renal function showed a significant inverse correlation between the serum EPO level and hemoglobin concentration, indicating an appropriate response to anemia. The chronic administration of recombinant human EPO raised the hemoglobin concentration of CRF mice, a therapeutic effect which was independent of the initial degree of anemia. These observations suggest that this animal model has wide applicability for the study of anemia secondary to CRF.

Topics: Anemia; Animals; Blood Cell Count; Blood Chemical Analysis; Bone Marrow; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Iron; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Recombinant Proteins

The purposes of this study were to determine whether (1) erythropoietin (Epo) gene expression could be stimulated, by severe hemorrhage, in both kidney and liver, at three stages of gestation (75-80, 106-112, and 140-142 days; term approximately equal to 150 days) in chronically-cannulated ovine fetuses and (2) whether the liver would compensate for the lack of kidneys at 110 days. Blood was removed (20% of estimated blood volume) at each of 0, 1, 19 h, and tissues collected at 24 h. In hemorrhaged fetuses (H) the liver mRNA levels were 2.7-, 5-, and 3-times that of control fetuses (C) at 78, 110 and 141 days, respectively. The kidney H:C ratios, for Epo mRNA, were 5, 6.4 and 43, respectively, at these three stages of gestation. In six fetuses at 108 days, nephrectomized 5-7 days before hemorrhage (HN) Epo mRNA increased 5-fold in the liver, and plasma Epo values were significantly lower (P < 0.05) than in intact (H). Thus hemorrhage stimulates increased Epo gene expression in both liver and kidney from mid-gestation, in the ovine fetus, but the liver does not compensate for the lack of kidneys at 110 days.

Topics: Animals; Body Weight; Erythropoietin; Gene Expression; Hemorrhage; Kidney; Liver; Nephrectomy; Organ Size; RNA, Messenger; Sheep

Topics: Anemia; Blood Donors; Blood Transfusion, Autologous; Blood Volume; Bone Marrow; Contraindications; Erythropoiesis; Erythropoietin; Female; Hemorrhage; Humans; Iron; Male; Nutrition Disorders; Recombinant Proteins; Safety

Over a 54-hour period, blood was removed from 8 adult sheep (body weight, 38.1 +/- 0.5 kg, mean +/- SEM) in 9 episodes, 5 on day 1, 3 on day 2, and 1 on day 3. Cumulative blood loss was 1,630 +/- 63, 2,380 +/- 71, and 2,693 +/- 69 ml on days 1, 2, and 3, respectively. Blood samples (20 ml) were collected from 5 control ewes (33.8 +/- 2.8 kg) at equivalent times. Over the first day, mean arterial blood pressure decreased in the hemorrhaged sheep from 101 +/- 2 mm of Hg to 76 +/- 5 mm of Hg, but returned to control values by the beginning of the second day and, thereafter, was not different from control values. Heart rate was increased after the first hemorrhage episode and remained high throughout the entire protocol. Over the entire period, there were statistically significant decreases in hematocrit, plasma osmolality, sodium, total calcium (P < 0.001), potassium, and chloride values (P < 0.05). There was no change in plasma phosphate, bicarbonate, creatinine, or magnesium concentrations and an increase in plasma urea nitrogen (P < 0.001) concentrations. Plasma arginine vasopressin concentration was increased significantly (P < 0.001) over the entire period. Plasma ACTH concentration was significantly (P < 0.05) increased over time, but only some values on day 1 were significantly outside the normal range of the control group data. Because of wide variation between sheep, the group data for aldosterone were not significantly different from control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Arginine Vasopressin; Bicarbonates; Blood Pressure; Blood Proteins; Carbon Dioxide; Drinking Behavior; Electrolytes; Erythropoietin; Female; Heart Rate; Hematocrit; Hemorrhage; Hormones; Hydrocortisone; Hydrogen-Ion Concentration; Osmolar Concentration; Oxygen; Partial Pressure; Sheep; Time Factors; Urea; Urination

Topics: Anemia; Blood Transfusion; Christianity; Erythropoietin; Hemorrhage; Humans; Religion and Medicine

This report describes the peri- and postoperative management of a patient with a critical blood loss (hemoglobin of 22 g/l) as a consequence of a surgical intervention, i.e. a radical resection of an advanced malignant gynecological tumor. The patient refused autologous and homologous blood transfusions for religious reasons (Jehovah's Witness). During surgery, hemodilution and cell salvage were used. Postoperatively she developed coagulopathy and hemorrhage with the lowest hemoglobin value of 22 g/l. The patient recovered under a therapy regimen of recombinant human erythropoietin and parenteral iron. The hemoglobin values returned to the lower normal range within 4 weeks. Consequences of hypoxia could not be seen.

Topics: Adult; beta-Thalassemia; Blood Loss, Surgical; Carcinoma, Squamous Cell; Christianity; Combined Modality Therapy; Erythropoietin; Female; Hemodilution; Hemoglobinometry; Hemorrhage; Humans; Iron; Postoperative Complications; Religion and Medicine; Uterine Cervical Neoplasms

The effect of aging on plasma erythropoietin (EPO) levels after acute hemorrhage was investigated in ovariectomized (Ovx) rats. Old (22 months), middle (mid)-aged (14 months) and adult (5-6 months) Ovx rats were studied. Rats were anesthetized with ether and bled by heart puncture (5 ml/kg). They were bled again after 1 h. The hematocrit and concentration of plasma EPO were determined for both bleedings. The prehemorrhage level of hematocrit was not altered by aging. The hematocrit level after hemorrhage was greater in old than in mid-aged (p < 0.05) and adult (p < 0.01) rats. The basal level of plasma EPO in old rats was higher than that in the adult rats (p < 0.05), but not in the mid-aged rats. The concentration of plasma EPO in response to hemorrhage was increased in all rats (p < 0.01). The hemorrhage-induced increase in plasma EPO was significantly greater in adult rats than in both mid-aged and old rats (p < 0.05). Our findings indicate that the basal level of plasma EPO is increased, but the hemorrhage-induced EPO secretion is diminished in ovariectomized rats during aging. These data then suggest that the tolerance to hemorrhage and the secretory function of EPO are changed by age.

Topics: Aging; Animals; Erythropoietin; Female; Hematocrit; Hemorrhage; Ovariectomy; Rats; Rats, Sprague-Dawley

Anemia was induced in rats by the development of a hemorrhagic ascites. These animals also bore solid tumors (DS-sarcomas) on the hind foot dorsum. The effects of two methods for anemia correction on oxygenation in the solid tumors were compared in this study. Anemia was corrected either chronically by erythropoietin administration (1000 IU/kg) over 14 days (EPO) or acutely by transfusion with red blood cells (TR). Non-anemic and untreated anemic animals served as controls. Tumor oxygenation was determined in anesthetized animals using polarographic needle electrodes and pO2 histography. The reduction in hematocrit and hemoglobin content found in anemic animals could successfully be corrected either by EPO or by TR. Anemia resulted in a worsening of tumor oxygenation which could partially be reversed by EPO or TR in small tumors (< 1.4 ml). In larger tumors (> or = 1.4 ml), neither method of anemia correction resulted in significant changes in tumor oxygenation.

Topics: Anemia; Animals; Blood Pressure; Carbon Dioxide; Erythrocyte Transfusion; Erythropoietin; Hematocrit; Hemoglobins; Hemorrhage; Hindlimb; Humans; Hydrogen-Ion Concentration; Male; Oxygen; Oxygen Consumption; Partial Pressure; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sarcoma, Experimental

Topics: Animals; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis, Extramedullary; Hemorrhage; Kupffer Cells; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C

1. A possible influence of the filling of the circulatory system on the plasma concentration of erythropoietin, which is the major regulator of erythrocyte formation, was investigated in conscious dogs. 2. Over an experimental period of 5 h, the animals were subjected to either haemorrhage (hypovolaemia), blood volume expansion (hypervolaemia), or exchange transfusion of blood with dextran (isovolaemic anaemia). 3. A reduction of blood volume by 20% induced by haemorrhage increased plasma erythropoietin levels approximately 1.5-fold in the absence of significant changes in haematocrit. 4. An expansion of blood volume by 12% induced by an intravenous infusion of dextran did not change plasma erythropoietin levels, although the haematocrit decreased by 0.04. 5. A reduction of the haematocrit by 0.12 in the absence of changes in blood volume induced by an isovolaemic exchange transfusion (dextran vs. blood) increased plasma erythropoietin levels approximately 3-fold. 6. Total renal oxygen supply did not change in any of the three experimental protocols. 7. These data indicate that in dogs the erythropoietin production rate is modulated by changes in blood volume, and suggest a possible role of erythropoietin in the regulation of blood volume.

Topics: Anemia; Animals; Blood Volume; Circadian Rhythm; Consciousness; Dextrans; Dogs; Erythropoietin; Exchange Transfusion, Whole Blood; Female; Hematocrit; Hemorrhage; Kidney; Male; Oxygen; Plasma Substitutes; Regional Blood Flow; Time Factors

Studies were performed to reexamine the response of erythropoietin (Epo) production to acute hypoxic stimuli in patients with end-stage renal disease (ESRD). In the absence of acute bleeding or hypoxia, the serum Epo level in ESRD was similar to that of normal subjects despite severe anemia. In 11 dialysis patients with acute bleeding, the decrease in the Hb level from 8.9 to 5.8 g/dL provoked a significant increase in serum Epo up to 52.2 times the normal value. The increase in serum Epo was associated with a significant increase in corrected reticulocyte. Systemic hypoxemia (PaO2 < 65 mm Hg) in 8 dialysis patients provoked a significant elevation in the serum Epo level up to 24.6 times the normal level. There was an inverse relationship between serum Epo and arterial PaO2 (r = -0.715). The serum Epo level in these patients declined to or near the normal value after recovery from acute hypoxic stress. These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.

Topics: Acute Disease; Adult; Aged; Anemia, Iron-Deficiency; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Oxygen; Partial Pressure; Renal Dialysis

We hypothesized that the fetus, in response to a moderately severe hemorrhage, would restore its plasma volume and red blood cells so that plasma volume would be returned to normal within 24 hours and red blood cell mass would be restored in 5 to 7 days.. Time-dated pregnant sheep (five control and six hemorrhage, gestational age 124 +/- 1 [SE] days) were subjected to a 10-day protocol. Fetal blood volume, plasma volume, red blood cell mass, and plasma protein mass were measured on protocol days 1, 3, 4, 6, 8, and 10. Fetal plasma erythropoietin and plasma iron concentrations were measured daily. On protocol day 3 the hemorrhage animals underwent a 120 ml fetal hemorrhage over 2 hours. Statistical analysis was by three-factor analysis of variance.. Control animals had a progressive increase in blood volume, plasma volume, plasma protein mass, and red blood cell mass throughout the 10-day protocol. The 2-hour hemorrhage removed 39.8% +/- 1.2% of the prehemorrhage blood volume. During the 7-day posthemorrhage recovery period fetal blood volume and red blood cell mass in the animals that were hemorrhaged expanded in parallel to, but remained below, that of the control animals. There was no difference in the expansion of fetal plasma volume or plasma protein mass between the two groups. After hemorrhage there was a nonsignificant increase in the fetal reticulocyte index in the animals undergoing hemorrhage. In response to the hemorrhage, erythropoietin levels increased and remained marginally elevated, whereas plasma iron levels decreased in the hemorrhaged animals relative to controls during the 7-day recovery period.. The normal expansion of plasma volume and plasma protein mass that occurs with fetal growth was not altered by a large fetal blood loss. However, in spite of a transient increase in plasma erythropoietin levels the fetuses undergoing hemorrhage did not restore their red blood cell mass or blood volume. These observations suggest that the ovine fetus is able to withstand a significant loss of red blood cells, but fetal transfusion may be needed to restore fetal red blood cell mass after a moderate-to-severe fetal hemorrhage.

Topics: Animals; Erythrocyte Volume; Erythrocytes; Erythropoietin; Female; Fetal Blood; Fetus; Gestational Age; Hematocrit; Hemorrhage; Plasma Volume; Pregnancy; Sheep

Erythropoietin (Epo) production was studied in adult sheep. Nine ewes, body weight (BW) 39 +/- 1.3 kg, were hemorrhaged a volume of blood equivalent to 1.6% BW, and sampled at 0, 2, 4, 6, 24 h. Oxygen content (O2 CT) decreased by 2.7 +/- 0.6 ml/dl at 2 h. Plasma immunoreactive (IR) Epo was only significantly increased at 24 h, from 18.5 +/- 3.5 to 40 +/- 10.7 mU/ml (mean +/- SEM). A further 5 ewes were bled extensively (2793 +/- 82 ml) over 54 h, and killed for Epo mRNA determination. The O2 CT decreased from 12.3 +/- 1.6 to 4.1 +/- 0.6 ml/dl, and plasma Epo increased from 15 +/- 4 to 1675 +/- 287 mU/ml. The sequence of ovine Epo cDNA was derived from the kidney RNA of a severely bled sheep using reverse transcription/polymerase chain reaction (RT/PCR), and from an ovine Epo genomic clone. The cDNA encodes a peptide of 194 amino acids, including a 27 amino acid signal peptide. The deduced amino acid sequence of sheep Epo shows 82%, 78% and 80% homology with mature Epos of human, mouse and monkey, respectively. The gene structure resembles closely those of human and mouse, with 5 exons and 4 introns. The expression of the ovine Epo gene in tissues from normal and hemorrhaged sheep was analysed by a competitive RT/PCR method. Epo mRNA was difficult to detect in liver from normal sheep, but was detectable at 0.01-0.04 amol/microgram total RNA in kidney from normal sheep. In the kidneys of severely bled sheep, the Epo mRNA levels (per micrograms total RNA) increased 400-1500-fold compared to that of normal kidneys, and were approximately 60-fold greater than those in the livers of the hemorrhaged sheep.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; DNA; Erythropoietin; Female; Gene Expression Regulation; Genes; Haplorhini; Hemorrhage; Humans; Kidney; Liver; Mice; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; Sequence Alignment; Sequence Homology, Nucleic Acid; Sheep; Species Specificity

Topics: Adult; Blood Transfusion; Cesarean Section; Christianity; Emergencies; Erythropoietin; Female; Hemorrhage; Humans; Postoperative Complications; Pregnancy; Pregnancy Complications; Religion and Medicine

In this study we examined erythropoiesis in the bone marrow and spleen of 9 to 12-day-old neonatal rats suckled by bleeding-induced anemic mothers. Quantitative evaluations of the spleen revealed a significant decrease in total numbers of nucleated RBC/mg spleen in 11-day-old pups nursed by the anemic mother which returned to control values by day 12. A significant reduction in total numbers of nucleated RBC/mg marrow was seen in both 11 and 12-day-old pups of anemic mothers when compared to control values. These results suggest that: 1. Ep is transmitted to suckling rats via the maternal milk; 2. Ep in the neonate exerts its influence predominantly at the level of the differentiated erythroid compartment probably by causing a shortening of the mean transit time of the proliferating erythroblast compartment and/or by decrease in the maturation time of the nonproliferating orthochromatic and reticulocyte compartments; 3. the regulation of erythropoiesis in the neonate differs from that in the adult.

Topics: Anemia; Animals; Animals, Newborn; Bone Marrow Cells; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hemorrhage; Maternal-Fetal Exchange; Milk; Pregnancy; Rats; Spleen

1. Basal and haemorrhage-stimulated erythropoietin (Epo) and ACTH levels were measured in the chronically cannulated immature ovine foetus (less than 125 days) by radio immunoassay (RIA). 2. Basal erythropoietin levels were found to be higher than those previously reported in the late gestation (greater than 130 days) ovine foetus, but were lower than those observed in the neonatal lamb. 3. In control foetuses (Protocol 1) the small degree of haemorrhage associated with the sampling procedure increased the plasma Epo values from 11.4 +/- 3.0 (n = 5) mU/mL to 23.8 +/- 4.3 mU/mL at 24 h (mean +/- s.e.m.). There was a significant monotonic increase with time (F = 16.4; d.f. 1,19; P = 0.001). An initial haemorrhage of approximately 10% blood volume (Protocol 2) increased plasma Epo values from 7.3 +/- 2.3 to 24.2 +/- 7.1 mU/mL (n = 3). 4. Haemorrhage of 20% fetal blood volume (Protocol 3) produced an increase in plasma Epo from 9.3 +/- 1.7 to 54.7 +/- 15.5 mU/mL at 6 h and to 57.6 +/- 7.3 mU/mL at 24 h (n = 5). By repeated measures ANOVA, the effect of the 20% haemorrhage was significant when compared with the control group (F = 7.32, d.f. 2,16, P = 0.006). There was a significantly greater decrease in haematocrit (F = 6.7, d.f. 2,20, P = 0.004) and haemoglobin (F = 5.0, d.f. 2,20, P = 0.013) in animals of Protocol 3 than in those of Protocol 1. 5. Fetal blood gases and plasma adrenocorticotropic hormone (ACTH) did not alter with haemorrhage, indicating the tolerance of the foetus to this degree of haemorrhage.

Topics: Adrenocorticotropic Hormone; Animals; Blood Gas Analysis; Embryonic and Fetal Development; Erythropoietin; Fetal Blood; Hemorrhage; Sheep

This study examines the response in plasma erythropoietin values to haemorrhage of 20% of the estimated blood volume in chronically cannulated ovine fetuses, of gestational ages 128-144 days. Blood samples were collected at 0, 2, 4, 6 and 24h with respect to the haemorrhage. In 5 control experiments there was no significant change in plasma erythropoietin concentration, across this time period, values being 6.1 +/- 2.3 and 6.4 +/- 2.4 mU/ml at 0 and 24h respectively. Values are mean +/- SEM. Haemorrhage reduced the haematocrit and haemoglobin values, significantly, to 83 +/- 6% and 85 +/- 4% (n = 5) of the initial value, respectively, but did not cause a statistically significant increase in plasma erythropoietin concentrations (7.2 +/- 2.4 and 20.7 +/- 8.2 mU/ml; P = 0.131). A larger degree of haemorrhage, in four fetuses reduced the haematocrit to 64 +/- 2.8% of initial, over 24-54h and increased erythropoietin values very significantly (from 11.9 +/- 3.6 to 91 +/- 8.3 mU/ml; P = 0.001).

Topics: Adrenocorticotropic Hormone; Animals; Blood Gas Analysis; Erythropoietin; Fetus; Gene Expression Regulation; Gestational Age; Hematocrit; Hemoglobins; Hemorrhage; Sheep

In all mammalian species studied the haematocrit (hct) declines after birth in the absence of any known nutritional deficiencies. The glycoprotein hormone, erythropoietin (Epo), is essential for normal red blood cell production. The aims of this study were 1) to investigate the changes in plasma Epo during the normal post-natal decrease in hct in lambs; 2) to compare the effects of chronic and acute haemorrhage in neonatal lambs; and 3) to test the hypothesis that the Epo response to haemorrhage is blunted in the neonatal period. Twenty-one lambs (0-9 weeks of age) were studied; group I (n = 8) were used to document normal post-natal changes (98 samples); group II (n = 7) lambs were haemorrhaged repetitively during weeks 3-6 (95 samples); group III (n = 6) lambs were bled once in the first 3-week period. In the group I (control lambs) the hct decreased from 30.6 +/- 1.3 (weeks 1 & 2) to a nadir of 23.2 +/- 0.8 (75.8% of initial value) in the 6th week, and the plasma Epo declined from 25.7 +/- 4.9 (week 1) to 12.3 +/- 1.0 mU/ml (week 6). In group II, the lambs were bled repetitively, a total of 510 +/- 32 ml blood being removed during weeks 3-6, the hct was 18.7 +/- 0.8 (81% of hct at nadir in controls) in week 6, and Epo was 26.9 +/- 13.3 in week 3, 23.4 +/- 3.6 mU/ml in week 6.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Carbon Dioxide; Chronic Disease; Erythropoietin; Globins; Hematocrit; Hemorrhage; Hydrocortisone; Oxygen; Reference Values; Sheep

We have previously reported the successful development of hematopoietic chimerism after the in utero transplantation of fetal hematopoietic stem cells (HSC) in rhesus monkeys (Macaca mulatta). These animals exhibit sustained engraftment without immunosuppression or graft-versus-host disease (GVHD). To assess the functional response of the donor-derived erythropoietic population, we assayed the relative expression of donor and recipient hematopoietic progenitors in chimeric monkeys before and after anemic stress. Anemia in our chimeric animals resulted in increased erythropoietin (EPO) production comparable to controls. This was accompanied by changes in erythroid progenitor profiles, again similar to controls. Chimeric animals demonstrated normal reticulocytosis and reconstituted their hematocrit after hemorrhage at the same rate as controls. The donor-derived erythropoietic population exhibited normal responses to recipient regulatory signals and did not seem to expand at the expense of other hematopoietic lineages. Thus the proportions of engraftment for the myeloid and erythroid precursors in bone marrow and for blood lymphocytes remained stable. Our results demonstrate that the in utero transplantation of fetal HSC results in stable engraftment of donor erythropoietic progenitors, which appear to be fully integrated within the recipient's regulatory system. The abnormalities reported in the postnatal transplantation setting can then be attributed to immunologic reactions requiring conditioning myeloablative regimens. Fetal transplantation bypasses all these factors.

Topics: Anemia; Animals; Blood Cell Count; Chimera; Erythropoiesis; Erythropoietin; Female; Fetal Tissue Transplantation; Hematocrit; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hemorrhage; Lymphocytes; Macaca mulatta; Pregnancy; Reticulocytes

Perioperative administration of recombinant human erythropoietin (rEpo) may reduce the need for allogeneic blood transfusions by diminishing the time lag between blood loss and erythropoiesis and by generating more adequate Epo levels. The efficacy of pre- and postoperative rEpo was studied in rats subjected to blood loss (20% of the blood volume) and surgery (ileal resection). After 200 U rEpo/kg daily for 5 days postoperatively, hemoglobin had increased by 15.7 g/l in these rats but by 36.9 g/l in rEpo-treated controls without surgery (p less than 0.05), indicating an inhibitory effect of surgery on erythropoiesis. A course of 200 U rEpo/kg/day for 5 days, starting 4 or 2 days before operation and blood loss, resulted in significantly higher postoperative hemoglobin levels than in untreated controls. Such difference did not occur if rEpo treatment was begun on the day of operation. Prolonged (10-day) postoperative rEpo treatment was of minor benefit, inducing significant increase in hemoglobin and hematocrit only from day 8 onwards. The study indicates that rEpo is a promising agent to obviate need for perioperative blood transfusions, provided that the treatment is begun before operation.

Topics: Animals; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Hemorrhage; Ileum; Male; Postoperative Care; Preoperative Care; Rats; Rats, Inbred BN; Recombinant Proteins

Erythropoietin (EPO) mRNA levels were measured by ribonuclease (RNase) protection in organs from unstimulated rats and from animals after normobaric hypoxia or hemorrhagic anemia. Both liver and kidney responded to stimulation with large increases in EPO mRNA, but the response characteristic to graded stimulation was different. The liver responded poorly to mild normobaric hypoxia, accounting for only 2 +/- 1% of total EPO mRNA at 11% O2, but hepatic EPO mRNA levels increased steeply with more severe hypoxia so that at 7.5% O2 the liver contributed to 33 +/- 7% of the total. After hemorrhagic anemia, the liver also responded more strongly to more severe stimulation, but at all points it accounted for a significant proportion of total EPO mRNA, contributing 18 +/- 6% after removal of 2.5 ml (hematocrit 37.2 +/- 1.3%), increasing to 37 +/- 14% after venesection of 10.5 ml (hematocrit 15.8 +/- 0.8%). Studies of EPO mRNA in other organs confirmed that EPO production outside the liver and kidney were quantitatively insignificant in stimulated animals. However, the hypoxia-induced increases in EPO mRNA in brain, testis, and spleen suggest the existence of an oxygen-sensing mechanism at other sites.

Topics: Acute Disease; Anemia; Animals; Erythropoietin; Feedback; Hemorrhage; Hypoxia; Kidney; Liver; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Distribution

To assess the role of renal innervation in O2-dependent control of erythropoietin (EPO) formation, we have determined EPO mRNA levels in both kidneys of unilaterally denervated rats and sham-operated controls using RNase protection. To investigate whether possible effects of renal nerve input are related to the type of hypoxic stimulus and the degree of stimulation, animals were studied under basal conditions, after exposure to normobaric hypoxia (8% O2, 4 h) or CO (0.1%, 4 h), and after acute hemorrhage (decrease in hematocrit from 40.8 +/- 0.5 to 12.7 +/- 0.5% within 7 h; mean +/- SE, n = 6). Serum EPO levels rose on average 22-, 49-, and 48-fold under the three stimuli and were unaffected by unilateral denervation. Renal EPO mRNA levels in unilaterally denervated animals, when expressed in arbitrary units revealed by comparison with an external standard, were 7.0 +/- 1.5 vs. 6.3 +/- 2.0 (normoxia), 432 +/- 136 vs. 451 +/- 156 (normobaric hypoxia), 971 +/- 93 vs. 930 +/- 120 (CO), and 604 +/- 170 vs. 689 +/- 203 (hemorrhagic anemia) in the intact vs. the denervated kidney (mean +/- SE, n = 3). Furthermore, there was no difference between EPO mRNA levels of either kidney of unilaterally denervated animals and levels in sham-operated controls. We conclude that renal nerve input plays no significant role in the control of the EPO gene under both basal and stimulated conditions.

Topics: Anemia; Animals; Blood Pressure; Carbon Monoxide; Cell Hypoxia; Denervation; Erythropoietin; Hematocrit; Hemorrhage; Histocytochemistry; Kidney; Male; Nucleic Acid Hybridization; Osmolar Concentration; Oxygen; Radioimmunoassay; Rats; Rats, Wistar; Ribonucleases; RNA, Messenger

Colony-forming efficiency (CFE) was used to monitor the proliferative response of alkaline phosphatase-positive rabbit bone marrow stromal cells to acute blood loss. The CFE of animals subjected to a 1% blood loss was 0.97 compared with 0.06 (p less than 0.01) in nonbled animals. Sera obtained from animals 10 days after an initial blood loss stimulated the CFE of marrow cultures from nonbled donors to the same degree as osteogenin. Erythropoietin and control sera (from nonbled animals) had no effect. Hence, acute blood loss and sera from bled animals stimulate proliferation of alkaline phosphatase-positive marrow stromal cell colonies. The agent(s) responsible is unknown but it is present in serum in response to blood loss. Confirmation of a specific effect on osteoprogenitor cells may warrant the designation "osteopoietin."

Topics: Animals; Blood; Bone Marrow; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Hemorrhage; Rabbits; Stem Cells

Retrospective studies have provided indirect evidence that allogeneic blood transfusion may adversely influence the prognosis of cancer patients. This effect may be prevented by using autologous blood transfusions. However, this involves preoperative donation of blood, the consequences of which are still unknown. The aim of the present study was to investigate the possible effects of blood loss on tumour growth and on NK-cell activity. An artificial lung metastasis model was used in the BN rat from which 20 per cent of the blood volume was taken at different time intervals. The results showed that blood loss, one day prior to tumour challenge, had a profound stimulating effect on tumour growth. After blood loss, the number of lung metastases was doubled as compared to controls. This tumour-promoting effect could be prevented by an immediate plasma transfusion, but not by evoking a normal haemoglobin level after blood loss by pretreatment with recombinant erythropoietin (rEpo). The NK-cell activity of spleen cells was significantly depressed, 24 hours after blood loss. At a 50:1-lymphocyte-to-target cell ratio, the NK-cell activity dropped from 25.3 per cent in controls to 9.3 per cent in experimental animals. Since NK-cells are assumed to play a role in the clearance of tumour cells from the circulation, the enhanced tumour growth observed after blood loss might be caused by this depression.

Topics: Animals; Cell Division; Erythropoietin; Hemorrhage; Killer Cells, Natural; Male; Neoplasms, Experimental; Rats; Rats, Inbred BN; Recombinant Proteins; Transfusion Reaction

The metabolic fate of erythropoietin (EPO) remains unknown. Urinary excretion does not appear to play a major role and liver catabolism has been shown to occur only after terminal sugars on the hormone have been removed. However, it has been proposed that EPO is eliminated by consumption in the bone marrow. In order to examine the extent of such consumption we measured the half-life of radioidinated recombinant EPO injected intravenously (IV) to rats with bone marrows suppressed by cyclophosphamide or hypertransfusion and marrows stimulated by phenylhydrazine or bleeding. The mean half-life or erythropoietin in normal rats was 179 +/- 16 min, with similar half-lives found in the other rats regardless of decreased or increased bone marrow activity. The results indicate that it is unlikely that erythroid activity determines EPO life span and catabolism.

Topics: Animals; Bone Marrow; Cyclophosphamide; Erythropoietin; Half-Life; Hemorrhage; Hyperplasia; Injections, Intravenous; Male; Phenylhydrazines; Rats; Rats, Inbred Strains; Recombinant Proteins

In order to evaluate the possibility of using recombinant human erythropoietin (rhEpo) for the prevention and correction of anemia due to blood loss and as an adjuvant for autologous blood transfusion, its preventive and therapeutic effects were evaluated in beagles in which anemia was induced by repeated phlebotomies. Two hundred U/kg of rhEpo were administered i.v. four or nine times every two weeks for six weeks. Phlebotomies (25 ml/kg of body weight) were conducted three times at two-week intervals. rhEpo was found to successfully prevent and correct anemia caused by the phlebotomies. Concurrent administration of iron increased efficacy. The findings obtained in the present study suggest that rhEpo is useful both for the treatment of anemia caused by blood loss due to surgery and as an adjuvant therapy for pre-deposit autologous blood transfusion.

Topics: Anemia; Animals; Dogs; Drug Therapy, Combination; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hemoglobins; Hemorrhage; Humans; Iron; Male; Recombinant Proteins

A markedly anaemic, haemodialysis patient with a mixed deficiency of erythropoietin (EPO) and iron developed a life-threatening worsening of anaemia during an episode of severe rectal bleeding. Despite frequently recurring episodes of considerable ischaemic cardiac pain, the patient's religious conviction did not permit blood transfusion. Consequently, combination therapy with both recombinant human EPO (rhEPO) and oral iron was instituted. In this haemodialysis patient, the vitally significant replacement therapy of rhEPO and iron was followed by a steady and uncomplicated restoration of subnormal hematocrit and complete disappearance of cardiac ischaemia.

Topics: Adult; Erythropoietin; Hemoglobins; Hemorrhage; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

A mathematical model of erythropoietic cell production and its regulation process has been proposed in a preceding paper. It is primarily based on the assumption that the number of cell divisions taking place in the CFU-E and erythropoietic precursor stages is regulated depending on the oxygen supply of the tissue. Quantitative dose-response relationships for in vivo erythropoiesis are suggested. Here, we demonstrate that this model adequately reproduces data obtained in situations of stimulated erythropoiesis in mice and rats. In detail, this implies a quantitative description of the following processes: (1) Changes in tissue oxygen tension (Pto2) following removal of red cells (bleeding, haemolytic anaemia) or increase in plasma volume (dilution anaemia) or decrease in atmospheric oxygen pressure (hypoxia). (2) Pto2 dependent erythropoietin (EPO) production. (3) Dose-response of EPO on erythropoietic amplification (up to two to four additional mitoses). (4) The changes of the marrow transit time. Model simulations are compared with experimental data for changes of erythropoiesis during hypoxia, EPO-injection, and different forms of anaemia. A satisfactory agreement suggests that the model adequately describes and correlates different direct and indirect ways to stimulate erythropoiesis. It quantifies the role and relative contribution of the haematocrit, haemoglobin concentration, atmospheric oxygen pressure, tissue oxygen pressure, and plasma volume as triggers in erythropoietic stimulation under various conditions. Furthermore, the model may allow to optimize the scheme of EPO-administration and to find the maximum increase of erythropoiesis for a given amount of erythropoietin.

Topics: Anemia; Animals; Blood Volume; Erythropoiesis; Erythropoietin; Hematocrit; Hematopoietic Stem Cells; Hemorrhage; Hypoxia; Mice; Phenylhydrazines; Rats; Reticulocytes

Topics: Adult; Deamino Arginine Vasopressin; Erythropoietin; Female; Hemorrhage; Humans; Uremia

Patients with uraemia have a defect of primary haemostasis expressed as long skin bleeding times and reduced platelet adhesion to the arterial subendothelium. Transfusion of red cells shortens the bleeding time and stops bleeding symptoms in uraemia. This study investigated whether the efficacy of recombinant human erythropoietin in correcting anaemia and the improvement in haemostasis are correlated. Recombinant human erythropoietin was given to seven consecutive patients with chronic uraemia, a history of bleeding, severe anaemia (haematocrit below 23%), and long bleeding times (above 19 min). The progressive rise in haematocrit induced by increasing doses of recombinant human erythropoietin was paralleled by a pronounced shortening of the bleeding time. Platelet adhesion to the subendothelium of human umbilical arteries, very low before the study, increased greatly in all patients and became normal in six. None of the patients bled during the study period.

Topics: Adult; Anemia; Erythropoietin; Female; Hematologic Tests; Hemorrhage; Hemostasis; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Injection of cobalt into rats resulted in erythropoietin (EPO) mRNA accumulation in the kidney. The same response was obtained upon bleeding. No EPO mRNA was detected in the spleen, salivary gland, or thymus following cobalt injection or bleeding. In some animals, but not in others, EPO mRNA was also expressed in the liver in response to cobalt injection. Time course studies showed that message appearance begins sometime between 3 and 6 h after cobalt injection. This correlated very well with the EPO concentration in the circulation; EPO levels in the circulation were the same as those of controls at 3 h but increased to six- to sevenfold that of controls by 6 h after cobalt injection. The mature EPO mRNA in the rat and mouse comigrated with the 18S rRNA, indicating that it is about 1,850 nucleotides in length.

Topics: Animals; Cobalt; Erythropoietin; Gene Expression Regulation; Hemorrhage; Kidney; Leukemia, Erythroblastic, Acute; Liver; Male; Rats; RNA, Messenger; Time Factors

The balance of erythropoietin production by the dog kidney and liver was studied during controlled normoxic perfusion. The hormone production was stimulated by acute posthemorrhagic anemia (bloodletting of 25% total blood volume) combined with subcutaneous injection of cobaltous chloride (250 microM/kg body weight). The increase in erythropoietin level was revealed in posthypoxic animal perfusate after 6 hours of perfusion. The amount of hepatic erythropoietin was shown to be 2.5 times higher than that excreted by kidneys.

Topics: Animals; Cobalt; Dogs; Erythropoiesis; Erythropoietin; Hemorrhage; Kidney; Liver; Male; Mice; Mice, Inbred CBA; Perfusion; Polycythemia

The properties of early (BFUen) and late (CFUen) erythropoietin-independent progenitors were studied in bone marrow plasma clot cultures of mice. Syngeneic serum was used as a stimulant of colony formation. It was revealed that serum from polycytemic mice did not alter the efficacy of cloning the erythroid progenitors. Varying effects produced on erythropoiesis in vivo did not significantly change the number of CFUen and BFUen, with the exception of posttransfusion polycytemia where the number of CFUen showed a statistically significant rise. Assessment of radiosensitivity and proliferative activity of the erythroid progenitors showed that for CFUen Do=206 rad and n=1.3; for BFUen Do=118 rad and n=1.4; the proportion of proliferating CFUen was 42% +/- 12.5 and that of BFUen 46% +/- 4.5. The data obtained confirm the hypothesis of the erythropoietin-independent nature of the erythroid progenitors expressed under the culture conditions used.

Topics: Animals; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Hemorrhage; Hybridization, Genetic; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Polycythemia

Hemorrhage against the background of bilateral nephrectomy led to the erythroid reaction of the rat bone marrow despite reduction of erythropoietin concentration in the circulating blood. Similar effect occurred when the nephrectomy was followed by ablation of salivary and lacrimal glands. Aqueous extracts of salivary and lacrimal glands as well as of muscular tissue had no effect on medullary hemopoiesis of nefrectomized animals but increased the amount of the peripheral blood reticulocytes and the serum erythropoietic activity.

Topics: Animals; Erythropoietin; Female; Hemorrhage; Lacrimal Apparatus; Muscles; Nephrectomy; Rats; Salivary Glands

Topics: Anemia; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Hypersplenism; Iron; Kinetics; Renal Dialysis; Uremia

Topics: Alkylating Agents; Erythropoietin; Hematocrit; Hemorrhage; Humans; Leukemia; Polycythemia; Polycythemia Vera; Smoking; Thromboembolism

The kinetics of the CFU population and of erythropoiesis were investigated in the AKR strain mouse prior to the onset of thymic leukaemias: haemopoiesis was compared in syngeneic AKR, semi-allogenic C3H and (C3H X AKR) F1 mice injected with AKR stem cells. These experiments demonstrate that the reduction in The number of spleen colonies previously described by Perkins et al. (1971) in syngeneic hosts, as compared to semi-allogenic C3H hosts, is actually related to defective erythropoiesis resulting from a dysfunction of the AKR haemopoietic inductive microenvironment (HIM). Erythropoietin secretion is normal in AKR mice. The early haemopoietic events related to the stem cell: lodgement of the CFU ('f' factor) and doubling time, are not disturbed, but the onset of CFU proliferation is markedly delayed in the AKR strain. The main expression of the AKR HIM dysfunction is a significant reduction in the number of erythroid (E) colonies and an impaired output of red blood cells per E-colony in the syngeneic host as compared to the allogenic one. In addition, data indicate that a weakly histo-incompatible system, such as that in C3H and hybrid hosts, does not interfere with the stages of haemopoiesis except by lengthening the doubling time of the CFU. The results, on the whole, emphasize the prevalent influence of HIM.

Topics: Animals; Bone Marrow; Cell Division; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematopoietic Stem Cells; Hemorrhage; Kinetics; Male; Mice; Mice, Inbred AKR; Mice, Inbred C3H

The effect of bleeding on spleen colony-forming units (CFU-S) and on in vitro colony-forming cells with colony-stimulating factor (CFU-C) and erythropoietin (CFU-E) has been evaluated. The in vivo and in vitro colony-forming cells of the bone marrow show a decrease which for the CFU-E, CFU-C follows a short-lived increase. In the spleen, all progenitor cells assayed have shown a significant and sustained increase.

Topics: Animals; Cell Division; Clone Cells; Colony-Stimulating Factors; Erythropoietin; Hematopoietic Stem Cells; Hemorrhage; Mice; Mice, Inbred Strains; Spleen

Topics: Anemia; Animals; Blood Transfusion; Erythrocytes; Erythropoietin; Hemorrhage; Male; Phenylhydrazines; Polycythemia; Rats

Using a methylcellulose clonal cell culture technique, we examined serial changes in erythropoietic precursors in the femur, spleen, and blood of mice prepared with bleeding, erythropoietin injections, or hypertransfusion with packed red blood cells. Significant changes were observed for all hemopoietic organs in the number of erythropoietic burst-forming units (BFU-E) and erythrocytic colony-forming units (CFU-E). In mice prepared with bleeding or erythropoietin injections, the serial changes of BFU-E and CFU-E were similar to but less striking than those seen in mice with phenylhydrazine-induced anemia. The transient decline in the femoral BFU-E coincided with the temporary increase in the splenic and blood BFU-E. A more pronounced increase in CFU-E was noted in the femur and spleen of these mice. In hypertransfused mice, the direction of the changers in the erythropoietic precursors was opposite. While femoral BFU-E increased mildly, a significant drop was noted in the splenic and blood BFU-E. Both femoral and splenic CFU-E declined and remained low while erythrocytosis presisted. Next, we examined the proliferative state of the erythropoietic precursors in the marrow and spleen using short-term incubation with high specific tritiated thymidine. In the marrow and spleen of normal mice, the BFU-E and CFU-E in the DNA synthetic phase was about 36 and 74%, respectively. Neither induction of anemia with phenylhydrazine hydrochloride nor polycythemia with hypertransfusion caused changes in the proliferative state of the precursors. These results indicate that the serial changes in the number of BFU-E represent migration of BFU-E from marrow to spleen rather than BFU-E proliferation. Marrow CFU-E increased in anemic mice and decreased in polycythemic mice without changes in their proliferative state. It is possible that the target of erythropoietic stimulation in mice may be cells at maturational stages intermediate between BFU-E and CFU-E.

Topics: Animals; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Cell Division; Cells, Cultured; Clone Cells; Erythrocytes; Erythropoiesis; Erythropoietin; Hemorrhage; Male; Mice; Mice, Inbred Strains; Phenylhydrazines; Spleen

Topics: Animals; Erythropoietin; Hemorrhage; Hypoxia; Rabbits

The effects of hemorrhage, hypoxia, or a preparation of erythropoietin on platelet production were investigated by measuring incorporation of selenomethionine-75Se (75SeM) into the platelets of rabbits or mice. Rabbits that were bled daily for 5 days had a significant increase in the platelet count, 48 hours after cessation of hemmorrhage, that coincided with a threefold increase in isotope incorporation into platelets. Mice that were bled daily for 3 days also had significantly higher platelet counts and a 38 per cent increase in incorporation of isotope into platelets, 3 days after the last hemorrhage. Normal rabbits, injected with plasma from repeatedly bled, anemic, and moderately thrombocytopenic rabbits, had a 58 per cent greater maximum incorporation of 75SeM than did control animals. Mice exposed to hypoxia for 6 days had a mean platelet count 23 per cent lower than normal controls, but no change in incorporation of 75SeM into platelets. Plasma from hypoxic mice did not stimulate platelet production when injected into normal mice. A preparation of human urinary erythropoietin (15 to 30 U. per mouse or 30 to 120 U. per rabbit) significantly increased incorporation of isotope into the platelets of normal mice and rabbits. The results demonstrated that hemorrhage, but not hypoxia, is associated with increased thrombopoietic activity in plasma. However, large doses of preparations of human erythropoietin contained detectable thrombopoietic activity.

Topics: Animals; Blood Platelets; Erythropoietin; Hematopoiesis; Hemorrhage; Hypoxia; Mice; Plasma; Rabbits; Selenomethionine; Thrombocytopenia

Topics: Adolescent; Adult; Aged; Anemia; Erythropoietin; Female; Hemagglutination Inhibition Tests; Hemorrhage; Humans; Kidney Failure, Chronic; Male; Metrorrhagia; Middle Aged; Uremia

The mechanism of erythropoietin (Ep) production after acute haemorrhage has been thought to be due to a reduction in blood volume and tissue perfusion leading to tissue hypoxia. In the present study we have evaluated the effect of acute haemorrhage in the rat on the acid-base status, the red cell affinity for oxygen in vivo, and Ep production. Within a few hours after acute blood loss there was a respiratory alkalosis with an increase in blood pH, a decrease in pCO2 and an increase in the red cell affinity of Hb for oxygen in vivo that was temporally related to an increase in Ep production. Within 24 h after the acute haemorrhage, the blood pH AND PCO2, red cell affinity for oxygen in vivo, and Ep level returned towards normal. The decrease in in vivo red cell affinity for oxygen was associated with an increase in red cell 2,3-DPG levels and a decrease in Ep production.

Topics: Acid-Base Imbalance; Acute Disease; Alkalosis, Respiratory; Animals; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Female; Hemorrhage; Oxyhemoglobins; Partial Pressure; Rats

The function of phenylhydrazine (PHZ) hemolysis in ameliorating the anemia induced in mice by a slow-acting strain of Rauscher leukemia virus (RLV-A) was described. After cessation of treatment with PHZ, mid-stage RLV-A-infected, anemic mice responded with massive reticulocytoses and a rebound in hematocrit above control levels. RLV-infected mice, subjected to PHZ-induced hemolysis or phlebotomy, produced high levels of plasma erythropoietin (Ep); this suggested that Ep mediated the PHZ-induced differentiation. In addition, administration of exogenous Ep induced a wave of erythroid maturation in RLV-infected anemic mice, which indicated that virus-infected erythroid precursors could still respond to the hormone governing normal differentiation.

Topics: Anemia; Animals; Cell Differentiation; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemorrhage; Male; Mice; Mice, Inbred BALB C; Phenylhydrazines; Rauscher Virus; Reticulocytes; Spleen; Splenectomy

Using the post-hypoxic mouse method of assay, values for erythropoietin in the plasma of patients with chronic renal failure were equal to, or greater than, normal values. Results suggest that the source of erythropoietin may be primarily extrarenal. Normal renal tissue, provided in the assay by the intact mouse, is required for activation of the hormone. There still remains to be explained the enhanced erythropoietic response to haemorrhage or hypoxia that can occur in anephric man.

Topics: Erythropoietin; Hemorrhage; Humans; Hypoxia; Kidney Failure, Chronic; Methods; Reference Values

Topics: Administration, Oral; Anemia, Hypochromic; Animals; Ascorbic Acid; Biological Transport; Body Weight; Diet; Erythropoietin; Female; Genetic Linkage; Hematocrit; Hemorrhage; Hypoxia; Injections, Intraperitoneal; Intestinal Absorption; Iron; Iron Radioisotopes; Male; Mice; Mice, Inbred Strains; Phenobarbital; Sex Chromosomes; Statistics as Topic

Hematopoiesis in the grey collie dog undergoes periodic fluctuations which involve reticulocytes, granulocytes, platelets, lymphocytes, and monocytes. This syndrome is inherited in an autosomal recessive manner and can be transmitted or abolished by appropriate bone marrow transplantation experiments, thus demonstrating this to be a primary marrow defect. Investigation of humoral regulation in this setting indicates that serum erythropoietin (ESF) also undergoes cyclic fluctuation and that shortly after the increase and peak in serum ESF levels recognizable red cell precursors appear in the marrow. Erythropoiesis in the grey collie is reciprocally related to the blood O2 carrying capacity. With phlebotomy, ESF activity and reticulocytes increase but continue to cycle, while hypertransfusion eliminates reticulocyte production completely. Neither phlebotomy nor hypertransfusion alter the underlying cycle time (11-12 days) nor influence the peaks of peripheral blood granulocytes. Thus, in these experiments, no direct evidence of competition between reticulocyte and granulocyte production is observed. In vitro studies of canine hemoglobin synthesis fail to demonstrate evidence of an inhibitor to ESF. These results indicate that periodic fluctuation of serum ESF is an integral part of the grey collie syndrome and are most consistent with some form of feedback regulation of ESF production.

Topics: Animals; Blood Transfusion; Dogs; Erythrocyte Count; Erythropoiesis; Erythropoietin; Granulocytes; Hematocrit; Heme; Hemoglobins; Hemorrhage; Iron; Iron Radioisotopes; Leukocyte Count; Reticulocytes

Topics: Adaptation, Physiological; Androgens; Anemia; Anemia, Hemolytic; Deficiency Diseases; Diet Therapy; Erythrocytes; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Kidney Failure, Chronic; Nephrectomy; Oxygen Consumption; Renal Dialysis; Uremia; Vitamins

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Nucleus; Cobalt; Depression, Chemical; Erythropoietin; Hemorrhage; Kidney; Microsomes; Mitochondria; Mitosis; Rabbits; Rats; Stimulation, Chemical; Tissue Extracts

Topics: Anemia; Animals; Autopsy; Bone Marrow Cells; Bone Marrow Transplantation; Erythropoiesis; Erythropoietin; Escherichia coli; Female; Haplorhini; Hematoma; Hematopoiesis; Hemorrhage; Iron Radioisotopes; Leukocyte Count; Leukocytes; Leukocytosis; Leukopenia; Macaca; Male; Mice; Nandrolone; Nitrogen Mustard Compounds; Polysaccharides, Bacterial; Radiation Injuries, Experimental; Time Factors; Transplantation, Autologous

Topics: Animals; Bone Marrow; Bone Marrow Cells; Calcium; Cell Count; Erythropoietin; Hemorrhage; Male; Mitosis; Parathyroid Glands; Rats

Topics: Anemia; Animals; Bone Marrow Cells; Cell Differentiation; Cell Nucleus; Centrifugation, Density Gradient; Erythrocyte Aging; Erythrocyte Count; Erythrocytes; Erythrocytes, Abnormal; Erythropoietin; Hemorrhage; Microscopy, Electron; Rabbits; Reticulocytes; Ribosomes; RNA; Time Factors

Topics: Anemia, Macrocytic; Animals; Atmospheric Pressure; Blood Volume; Bone Marrow Cells; Erythropoiesis; Erythropoietin; Genotype; Hematocrit; Hemorrhage; Hypoxia; Mice; Mice, Inbred Strains; Mutation; Phenylhydrazines; Spleen

Topics: Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Macrocytic; Diagnosis, Differential; Erythrocytes; Erythropoietin; Half-Life; Hemorrhage; Humans; Iron; Neoplasms; Vitamin B 12 Deficiency

Topics: Animals; Biological Assay; Erythropoietin; Female; Haplorhini; Hemorrhage; Hot Temperature; Humans; Hypoxia; Infant, Newborn; Injections, Intramuscular; Injections, Intravenous; Iron Isotopes; Kidney; Male; Mice; Nephrectomy; Papio; Testosterone

Topics: Animals; Blood Transfusion; Bone Marrow; Depression, Chemical; Erythropoiesis; Erythropoietin; Hematocrit; Hemorrhage; Hypoxia; Iron; Iron Isotopes; Liver; Lymph Nodes; Male; Mice; Spleen; Stimulation, Chemical

The level of nucleoside deaminase was determined in extracts of mouse tissues obtained during a period of accelerated erythropoiesis induced by hypoxia, hemorrhage, or the injection of phenylhydrazine. Under these conditions a striking (10- to 100-fold) elevation of the enzyme activity occurred in the spleen. Similar results were obtained with the injection of purified erythropoietin. In control animals, only a trace of nucleoside deaminase activity was detected in the blood. During the reticulocyte response which followed erythropoietic stimulation, there was a sharp increase in the blood level of nucleoside deaminase, which rose up to 120 times that of control animals. By differential centrifugation, the enzyme was localized to the reticulocyte-rich fraction. Erythrocyte nucleoside deaminase remained elevated even after the reticulocyte count had fallen to normal in the phenylhydrazine-treated mice or to zero after the cessation of hypoxia. There was a very gradual decline in the enzyme activity in the blood which fell to the barely detectable control levels about 45 days after the initial reticulocyte response, a time period which corresponds to the survival of the mouse red blood cell. The persistence of high levels of nucleoside deaminase for the full life span of a generation of erythrocytes formed during stress, viewed in contrast to the virtual absence of the enzyme from normal erythrocytes of all ages, represents an enzymatic difference between the normal red blood cell and the cell produced under conditions of accelerated erythropoiesis.

Topics: Aminohydrolases; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Friend murine leukemia virus; Guinea Pigs; Hematocrit; Hemolysis; Hemorrhage; Hypoxia; Male; Mice; Nucleic Acids; Nucleosides; Phenylhydrazines; Rabbits; Rats; Reticulocytes; Spleen; Stress, Physiological; Time Factors

Topics: Animals; Blood Transfusion; Bone Marrow; Culture Techniques; Erythropoiesis; Erythropoietin; Hemorrhage; Mitosis; Rabbits; Rats; Reticulocytes

Topics: Animals; Cobalt; Dogs; Erythropoietin; Female; Hemorrhage; Hypoxia; Iron Isotopes; Kidney; Kidney Transplantation; Male; Mice; Testosterone; Transplantation, Autologous

Topics: Animals; Bone Marrow; Carbon Isotopes; Cobalt; Enzymes; Erythrocytes; Erythropoietin; Glycine; Heme; Hemorrhage; Histones; Iron; Iron Isotopes; Liver; Lyases; Lymphoma, Non-Hodgkin; Lysine; Phenylhydrazines; Porphyrins; Radiation Effects; Rats; Reticulocytes; Spleen

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Nucleus; Cobalt; DNA; Enzyme Repression; Erythropoiesis; Erythropoietin; Hemorrhage; Phenylhydrazines; Phosphorus; Phosphorus Isotopes; Rabbits; Ribosomes; RNA; RNA, Transfer; Stimulation, Chemical

Topics: Animals; Dogs; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Methods

Topics: Aging; Animals; Bone Marrow Cells; Carbon Isotopes; Cell Differentiation; Cytoplasm; Dactinomycin; Erythrocytes; Erythropoietin; Glycine; Hemorrhage; In Vitro Techniques; Rabbits

Topics: Adult; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemorrhage; Humans; Kidney; Male; Nephrectomy

Topics: Acetates; Amino Acids; Anemia; Animals; Dogs; Erythropoietin; Glycine; Hemorrhage; Iron; Kidney; Levulinic Acids; Liver; Myocardium; Phenylhydrazines; Porphyrins; Spleen

Topics: Anemia; Anemia, Hemolytic; Animals; Erythropoiesis; Erythropoietin; Female; Genetics; Hemorrhage; Hypoxia; Iron; Iron Isotopes; Male; Mice; Oxygen; Partial Pressure; Phenylhydrazines

Topics: Animals; Cobalt; Culture Techniques; Erythropoiesis; Erythropoietin; Hemorrhage; Iron; Mice; Organ Size; Radiation Effects; Spleen; Splenectomy; Testosterone

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hemorrhage; Hypothalamus; Hypoxia, Brain; Ischemic Attack, Transient; Rats

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Transfusion; Erythropoietin; Hemorrhage; Hypoxia; Immune Sera; Male; Nephrectomy; Polycythemia; Rats; Splenectomy

Topics: Animals; Chlorpromazine; Dogs; Erythropoietin; Female; Glycolysis; Hemorrhage; Hypotension; Hypotension, Controlled; Kidney; Male; Manometry; Regional Blood Flow; Renal Veins; Splenectomy

Topics: Animals; Erythropoietin; Female; Hematocrit; Hemorrhage; Hydronephrosis; Hypotension; Iron Isotopes; Kidney Diseases; Male; Primates; Renal Artery Obstruction; Uremia

Topics: Animals; Erythropoiesis; Erythropoietin; Hemorrhage; Injections, Intravenous; Iron; Iron Isotopes; Rats

Following the successful replacement of diseased kidneys by renal homotransplants, regression of the anemia of chronic renal disease was found in five patients. Increased erythropoietic-stimulating activity was demonstrated in the serum of one patient seven weeks after renal transplantation when he suffered a severe hemorrhage. It is postulated that a renal homotransplant can produce enough erythropoietin to maintain a normal hemoglobin value and to respond to the stimulus of a sudden hemorrhage.

Topics: Anemia; Epoetin Alfa; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hemoglobins; Hemorrhage; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Reticulocytes; Transplantation, Homologous

The production of erythropoietin in dogs increased after they had been exposed to 300 rad of gamnma rays and then subjected to hemorrhage.

Topics: Animals; Dogs; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hemorrhage; Radiation Effects; Research

Topics: Anemia; Animals; Bone Marrow Cells; Epoetin Alfa; Erythropoietin; Hemorrhage; In Vitro Techniques; Iron; Polycythemia; Rabbits; Research; Reticulocytes; Sheep; Stem Cells; Tritium

Topics: Anemia; Anemia, Hemolytic; Animals; Biomedical Research; Bone and Bones; Bone Marrow; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobinometry; Hemorrhage; Humans; Iron Isotopes; Liver; Male; Pharmacology; Phenylhydrazines; Physiology, Comparative; Rabbits; Rats; Research; Spleen

Topics: Animals; Epoetin Alfa; Erythropoietin; Hemorrhage; Phenylhydrazines; Sheep

Topics: Epoetin Alfa; Erythropoietin; Hemorrhage; Humans; Serum