losartan-potassium and Thrombosis

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).. To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis

We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to the high hematocrit (HCT) achieved in the animals. However, similarly high HCT was achieved in both high-dose and low-dose groups, but there were no reported adverse events in the low-dose group suggesting HCT was not the sole contributing factor leading to toxicity. Our analysis indicated that increased dose, dose frequency, and dosing duration in addition to high HCT contributed to mortality and thrombosis. To further evaluate this relationship, the incidence of toxicities was compared in rats administered an experimental hyperglycosylated analog of recombinant human erythropoietin (AMG 114) at varying dosing schedules in 1-month toxicity studies. The incidence of mortality and thrombotic events increased in higher dose groups and when dosed more frequently, despite a similarly high HCT in all animals. The results from the investigative study and retrospective analysis demonstrate that ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration, and not solely dependent upon a high HCT.

Topics: Animals; Biomedical Research; Dogs; Erythropoiesis; Erythropoietin; Heart Valve Diseases; Hematinics; Hematocrit; Humans; Macaca fascicularis; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Retrospective Studies; Stomach Neoplasms; Thrombosis

In experimental models of acute myocardial infarction (AMI), erythropoietin (EPO) reduces infarct size and improves left ventricular (LV) function. However, in the clinical setting, the effect of EPO in AMI was unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of EPO to explore the safety and therapeutic effects of EPO in patients with AMI.. We identified reports of RCTs comparing EPO to placebo for AMI in adult humans in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Outcomes included all-cause mortality, major cardiovascular events, cardiac function by LV ejection fraction and infarct size.. We included 13 articles of RCTs with data for 1,564 patients. Erythropoietin therapy did not improve LV ejection fraction (weighted mean difference [WMD] 0.33, 95% CI -1.90 to 1.24, P = .68) and had no effect on infarct size, as measured by cardiac magnetic resonance imaging (WMD -0.12, -2.16 to 1.91, P = .90) or serum peak value of creatine kinase-MB (WMD -2.01, -25.70 to 21.68, P = .87). Erythropoietin treatment did not decrease the risk of total adverse cardiac events (relative risk [RR] 1.02, 0.65-1.61, P = .92). Erythropoietin treatment also failed to decrease the risk of heart failure (RR, 0.69, 0.27-1.72, P = .42) and all-cause mortality (RR 0.55, 0.22-1.33, P = .18). Moreover, EPO had no effect on the risk of stent thrombosis (RR, 0.69, 0.29-1.64, P = .40).. Erythropoietin in patients with AMI seems to have no clinical benefit for heart function or reducing infarct size, cardiovascular events, and all-cause mortality. Erythropoietin may not be a choice for patients with AMI.

Topics: Adult; Aged; Cardiovascular Agents; Drug Administration Schedule; Erythropoietin; Female; Heart Failure; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; Risk; Stroke Volume; Survival Rate; Thrombosis; Treatment Failure; Ventricular Function, Left

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

The synthesis of erythropoiesis-stimulating agents (ESAs), especially recombinant human erythropoietin, has provided a new therapeutic option for the treatment of patients with various forms of anemia, including that of chronic renal disease, malignancy, hematologic disorders, prematurity, and acquired immune deficiency syndrome. These agents are effective in improving the hematologic response and reducing the need for red blood cells transfusion, and they also appear to have a positive effect on some health-related quality-of-life indicators. The incidence of side effects and survival, however, remains highly uncertain, and several studies have recently highlighted the problem of an increased trend of tumor progression, mortality and thrombotic complications, especially venous thromboembolism, in patients undergoing therapy with ESAs. Specifically, the biological background underlying the prothrombotic effects of ESAs is multifaceted (polycythemia/hyperviscosity syndrome, hypertension, thrombocytosis, platelet hyperactivity, activation of blood coagulation) and context dependent, and it most likely requires the presence of additional prothrombotic factors. Nevertheless, this clinical and biological evidence supports the hypothesis that therapy with ESAs might not be ultimately beneficial or advantageous in patients with anemia of chronic disorders, and these drugs should not be routinely used as an alternative to blood transfusion unless future studies affirm safety and clinical benefits within these populations.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Thrombosis

Traumatic brain injury is a leading cause of mortality and long-term morbidity, particularly affecting young people. With our best therapies, one half of the patients with severe traumatic brain injury are never capable of living independently. Two interventions, which have real potential to improve neurological outcomes in patients with traumatic brain injury, are (i) very early induction of prophylactic hypothermia and (ii) exogenous erythropoietin therapy. There is substantial experimental evidence, a plausible biological rationale, and supportive clinical evidence from clinical trials to suggest a possible beneficial effect of prophylactic hypothermia and also for exogenous erythropoietin therapy in severe traumatic brain injury. Despite the recent guidelines and publications recommending these interventions, critical care clinicians should be conservative towards implementing these therapies outside clinical trials due to substantial efficacy and safety concerns. Nevertheless the high morbidity and mortality associated with severe traumatic brain injury (TBI) demands that we investigate the safety and efficacy of these promising potential therapies as a matter of urgency.

Topics: Animals; Body Temperature; Brain Injuries; Critical Care; Disease Models, Animal; Erythropoietin; Glasgow Coma Scale; Hematinics; Humans; Hypothermia, Induced; Neuroprotective Agents; Recombinant Proteins; Thrombosis; Treatment Outcome; Ultrasonography

Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Erythropoietin; Female; Humans; Models, Biological; Multiple Myeloma; Myeloproliferative Disorders; Neoplasms; Recombinant Proteins; Risk; Thrombophilia; Thrombosis; Venous Thromboembolism

Anaemia effects up to 90% of cancer patients, with more than 60% requiring blood transfusion during or after treatment. With the advent of recombinant human erythropoietins (rHuEPO), an alternative to red blood cell transfusion has become available. So far, three drugs have been approved for the treatment of anaemia in patients with malignancies (epoetin alfa, epoetin beta and darbepoetin alfa). New concepts for the use of erythropoietin in cancer patients include 3- and 4-weekly dosing, as well as loading-dose concepts. Important factors helping to judge the impact of erythropoietin in cancer treatment include pharmacoeconomics and better predictive factors. Lately, the influence of erythropoietin therapy on survival in cancer patients has been discussed very intensively, because conflicting data have emerged. Studies aimed at correcting anaemia in cancer patients had indicated a possible survival advantage of those patients receiving erythropoietin. In contrast, two recent trials aimed at correction of haemoglobin levels beyond anaemia reported a poorer survival of patients receiving erythropoietin. This might grossly be attributed to a higher risk of thrombosis in these patients. The largest systematic review on the use of erythropoietin in cancer patients undergoing treatment indicates a suggestive but not significant survival advantage of erythropoietin-treated patients. In addition, very recent results of a Food and Drug Administration meeting on safety and survival of patients treated with erythropoietin are presented.

Topics: Anemia; Economics, Pharmaceutical; Erythropoietin; Humans; Neoplasms; Prognosis; Recombinant Proteins; Risk Factors; Survival; Thrombosis

Erythropoietic agents are widely used to alleviate anemia in patients with cancer receiving chemotherapy. Over the past decade, the efficacy and safety of these agents in improving hemoglobin levels and reducing transfusion requirements in an oncology setting has been demonstrated in a number of clinical trials. The overall risk-benefit relationship of treatment with erythropoietic agents is favorable, and these agents represent a tremendous advance in anemia management. This review discusses prevalent issues and addresses key questions concerning the use of erythropoietic agents for the treatment of chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Humans; Thrombosis

A literature review on fish oil supplementation in the population undergoing chronic hemodialysis therapy suggests that supplementation may be beneficial for various challenges to health and well-being prevalent in this population. One study indicated that pruritus symptoms improved with fish oil supplementation, but not with supplementation with two other oils. In a study designed to determine whether fish oils could prevent vascular access graft thrombosis, graft patency rates were approximately 76% in the fish oil and approximately 15% in the placebo group (P>.03). In a pilot study, subjects given fish oil required 16% less erythropoietin and experienced a 3.6% increase in serum albumin levels. Some studies suggest that fish oil supplementation in hemodialysis patients is cardioprotective, with one study finding that "fish eaters" are half as likely to die as "non-fish eaters." Potential risks of supplementation include gastrointestinal distress, prolonged bleeding, and vitamin A toxicity, although the likelihood of serious side effects is probably low. Dietitians are in a position to advise physicians and/or patients regarding appropriate dosages and ways to minimize risks when supplementation seems warranted. Future research could compare the benefits of fish consumption with those of fish oil supplementation and explore the benefits of other n-3 fatty acid sources, such as flaxseed.

Topics: Cardiovascular Diseases; Catheters, Indwelling; Dietary Supplements; Erythropoietin; Female; Fish Oils; Humans; Kidney Failure, Chronic; Male; Pruritus; Renal Dialysis; Seafood; Serum Albumin; Thrombosis

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Topics: Anemia; Cardiovascular System; Cell Division; Chromogranins; Endothelium, Vascular; Erythropoietin; GTP-Binding Protein alpha Subunits, Gs; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nerve Tissue Proteins; Platelet Activation; Receptors, Erythropoietin; Recombinant Proteins; Thrombosis

Topics: Anemia; Apoptosis; Clone Cells; Disease Progression; Erythropoiesis; Erythropoietin; Female; Growth Substances; Hematologic Tests; Hematopoietic Stem Cells; Humans; Iron; Leukemia, Myeloid; Male; Myeloproliferative Disorders; Phlebotomy; Phosphorus Radioisotopes; Polycythemia Vera; Pregnancy; Pregnancy Complications, Hematologic; Receptors, Erythropoietin; Receptors, Growth Factor; Thrombocytosis; Thrombosis

Doping consists in the use of artificial means or substances with the unique aim of improving performance despite adverse effects on health. Amphetamines stimulate the central nervous system by increasing motivation and vigilance. Often consumed in association with analgesics, they increase the fatigue threshold during prolonged or repeated exercise. Addiction and dependency to these substances are extremely rapid. Side-effects include insomnia, exhaustion, violence and can lead to serious heart diseases. By enhancing capacity for intensive training, anabolic steroids improve strength, alertness and speed. This action is often further strengthened by the use of growth hormones DHEA and IGF-1. Extremely high dosage is used and is in no way comparable with natural secretions or those necessary to re-balance an exhausted glandular system. During prolonged endurance exercise, doping aims at improving the circulation of oxygen in the blood and thus its availability to the muscles. Firstly, the blood haemoglobin concentration was increased by blood transfusions. At present the production of red blood cells is stimulated by repeated injections of exogenous erythropoietin. The extreme viscosity of the blood leads to a risk of vascular thromboses and high blood pressure and accentuates greatly and sometimes even fatally the possibility of brachycardia which is common with sportsmen.

Topics: Amphetamines; Anabolic Agents; Bradycardia; Cardiovascular Diseases; Doping in Sports; Erythropoietin; Fatigue; Growth Hormone; Humans; Hypertension; Thrombosis

Data from four prospective, multicenter, randomized studies involving 869 major, elective orthopedic surgery patients were examined by means of a retrospective integrated analysis to evaluate whether perioperative Epoetin alfa use was associated with the occurrence of thrombotic/vascular events. The incidence of thrombotic/vascular events was similar between 619 patients treated with Epoetin alfa and 250 patients receiving placebo (7.4% versus 8.0%, respectively). Regression analyses identified age, cardiac history, hypertension, and cardiac medications, but not Epoetin alfa, as risk factors for thrombotic/vascular events. The analysis did not implicate an increase in the rate of rise in hematocrit or maximum hematocrit obtained prior to surgery as contributors to thrombotic events. Thus, Epoetin alfa, which enhances preoperative erythropoiesis and increases hematocrit, did not affect the probability of thrombotic/vascular events.

Topics: Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hematinics; Hematocrit; Hip; Humans; Incidence; Knee; Multicenter Studies as Topic; Placebos; Postoperative Complications; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Regression Analysis; Retrospective Studies; Risk Factors; Thrombosis; Vascular Diseases

Topics: Cardiovascular System; Catheters, Indwelling; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Physical Endurance; Quality of Life; Recombinant Proteins; Thrombosis

If one reviews the literature with zeal, it is increasingly apparent that few organs escape recruitment when IBD is chronic or progressive. Insights into mucosal pathophysiology have helped with understanding the more frequent extraintestinal manifestations, but the mechanisms attendant to the development of less common events (e.g. acute pancreatitis, concurrent gluten sensitive enteropathy, or active pulmonary disease) remain either poorly studied or obscure. It is particularly interesting, however, to read reports of abnormal pulmonary function, generally of the obstructive type, correlated to measurements of abnormal intestinal permeability in patients with either active pulmonary sarcoid or pulmonary involvement in Crohn's disease. It has been further speculated that similarities in the mucosal immune system of the lung and intestine are responsible for evidence of bronchial hyperreactivity in patients with active IBD. Finally, it is important to recognize that extensions of the inflammatory process are not restricted to the development of organ-based events but may be responsible for some of the most frequent systemic abnormalities detected in IBD patients. It is now also well confirmed that the cytokine environment in IBD can support activated coagulation and, in some clinical situations, overt vascular thrombosis. The cerebrovascular complications of IBD are well recognized and range from peripheral venous thrombosis to central stroke syndromes and pseudotumor cerebri. Reports of focal white matter lesions in the brains of patients with IBD or an increased incidence of polyneuropathy may be other clinical examples of regional microvascular clotting. Microvascular injury appears to be more ubiquitously present, with reports ranging from a speculated primary causative role (e.g., granulomatous vasculitis in the mesenteric circulation) to the utility of nailbed vasospasm, in Crohn's disease, as a clinical marker for disease activity. It is also reported that IL-6 suppression of erythropoietin production is a major feature of the chronic anemia seen in active IBD. Moreover, the capacity of peripheral monocytes from active IBD patients to secrete TNF and IL-8 is reported predictive for the degree of therapeutic response from recombinant erythropoietin. These collected observations constitute another excellent example of the symmetry between basic science and clinical utility. It is from the context of applied basic science that many future therapies wi

Topics: Anemia; Animals; Brain Diseases; Bronchial Hyperreactivity; Cerebrovascular Disorders; Crohn Disease; Cytokines; Disease Models, Animal; Erythropoietin; Humans; Inflammatory Bowel Diseases; Interleukin-6; Lung Diseases; Lung Diseases, Obstructive; Sarcoidosis; Thrombosis

Topics: Anemia; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Renal Dialysis; Seizures; Thrombosis

The treatment of renal anaemia by recombinant human erythropoietin (EPO) is now well established. Several studies have examined the pharmacokinetics and efficacy of the drug given intravenously, intraperitoneally and subcutaneously and there is increasing evidence that the subcutaneous route has several advantages including the requirement for a lower dose. It is also important to stress the need for careful determination of baseline iron status of all patients before commencing EPO therapy. In the long term the extremely high iron stores of transfusion dependent patients will disappear. In the short term, however, the majority of the patients whose serum ferritin is less than 100 micrograms/l will require iron supplementation to allow an appropriate haemoglobin response. Alternatively, a fall in transferrin saturation to less than 20% is certainly an indication for iron supplementation and if oral iron therapy is not adequate then intravenous preparations may have to be considered. Although the anaemia of renal failure can be fully corrected by EPO, partial correction may be sufficient to reverse the problems of reduced exercise capacity, myocardial ischaemia and cardiomegaly which are frequently associated with end-stage renal disease. Partial correction will also result in a lesser rise in whole blood viscosity and, in turn, possibly reduce hypertension, thrombosis and increased peripheral resistance and thus lessen the side effects of EPO therapy.

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Thrombosis

Topics: Anemia; Anemia, Hypochromic; Animals; Drug Hypersensitivity; Erythropoietin; Humans; Hyperkalemia; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Phosphates; Recombinant Proteins; Renal Dialysis; Seizures; Thrombosis; Uremia

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited.. Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125 U/L) at treatment start.. Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment.

Topics: Aged; Anemia; Disease-Free Survival; Erythropoietin; Female; Ferritins; Hematinics; Humans; Leukocyte Count; Male; Middle Aged; Primary Myelofibrosis; Sex Factors; Spain; Survival Rate; Thrombosis

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-β or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Biosimilar Pharmaceuticals; Chronic Disease; Epoetin Alfa; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Neoplasms; Prospective Studies; Recombinant Proteins; Thrombosis; Time Factors; Treatment Outcome; Young Adult

Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.. To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.. A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.. Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.. Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).. In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).. In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.. clinicaltrials.gov Identifier: NCT00378352.

Topics: Adult; Age Factors; Angioplasty, Balloon, Coronary; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Placebos; Recombinant Proteins; Stents; Stroke; Thrombosis; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Vascular access failure is a major cause of morbidity and hospitalization in hemodialysis populations worldwide. Erythropoietin (EPO) potentially can contribute to vascular access stenosis and occlusion by promoting intimal hyperplasia and thrombosis. Intravenous administration of EPO results in a severe, but transient, increase in drug concentration within the vascular access, whereas subcutaneous administration leads to a mild, but sustained, increase in the systemic circulation. The effect of route of administration of EPO on vascular access outcomes is uncertain.. Randomized controlled trial.. 78 Korean hemodialysis patients were randomly assigned to receive either intravenous (n = 40) or subcutaneous (n = 38) EPO.. EPO was administered during dialysis, and the dose was titrated to maintain hemoglobin levels between 9 to 12 g/dL. All patients received EPO 2 or 3 times/wk. Study duration was 4 to 77 months.. The primary end point was time to vascular access failure. Analysis was performed using Cox regression analysis.. The incidence of access failure was 4.7%/patient-year in the intravenous-therapy group and 12.0%/patient-year in the subcutaneous-therapy group, with an unadjusted hazard ratio of 3.24 (95% confidence interval, 1.31 to 8.00; P = 0.01). After adjustment for dialysis access type, vascular access age, previous intervention, serum phosphorus level, and diabetes mellitus, subcutaneous EPO administration was independently associated with increased vascular access failure (hazard ratio, 3.56; 95% confidence interval, 1.20 to 10.58; P = 0.02). There were no significant differences in either hemoglobin concentration or EPO dosage between the 2 groups during the study period.. Relatively small sample size and lack of complete symmetry between the 2 groups with respect to some baseline characteristics.. This study suggests that the risk of vascular access failure may be greater with subcutaneous compared with intravenous administration of EPO in hemodialysis patients.

Topics: Catheters, Indwelling; Drug Administration Routes; Equipment Failure; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Injections, Subcutaneous; Inpatients; Kidney Failure, Chronic; Korea; Male; Middle Aged; Morbidity; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Factors; Thrombosis; Time Factors; Treatment Outcome

PURPOSE, PATIENTS AND METHODS: This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin.. Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04-8.02, p value [p]=0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37-12.4, p=0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59-3.18, p=0.45).. Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Epidemiologic Methods; Erythropoietin; Female; Fibrinolytic Agents; Hematinics; Hemoglobins; Humans; Middle Aged; Neoplasm Metastasis; Prognosis; Recombinant Proteins; Thrombophlebitis; Thrombosis

Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC).. A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks.. Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment.. An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Canada; Carcinoma, Non-Small-Cell Lung; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Quality of Life; Recombinant Proteins; Thrombosis; Time Factors; Treatment Outcome

Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. We hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions.. In this prospective, randomized, placebo-controlled trial, we enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline.. As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86).. The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events. (ClinicalTrials.gov number, NCT00091910 [ClinicalTrials.gov].).

Topics: Adult; Aged; Critical Illness; Double-Blind Method; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Intensive Care Units; Kaplan-Meier Estimate; Length of Stay; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Respiration, Artificial; Thrombosis; Trauma Severity Indices; Wounds and Injuries

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.. Open-label, multicenter, randomized, parallel-group, phase 3 study.. Dialysis patients (age >or= 18 years).. Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly.. The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population.. Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated.. Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin.. Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

Topics: Anemia; Dose-Response Relationship, Drug; Drug Carriers; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Thrombosis; Treatment Outcome

Duplex sonography was used to assess functional features of arteriovenous fistula (AVF) for hemodialysis (HD). Internal diameter (ID), resistance index (RI) and blood flow (BF) velocity in feeding artery and in vein ofAVF, and venous BF volume were analyzed with purpose to determine the normal values. Presumed normal BF velocities are those of clinically well functioning shunts, allowing BF through HD lines of minimally 250 ml/min. Study included 66 nondiabetic HDpatients (30 women, 36 men), mean age 52-13 years, treated by HD for median 61 (4-252) months. Measurements in 47patients with clinically well functioning AVF were as followed: mean arterial ID 5.2 +/- 1.4 mm, median arterial RI 0.3 (0.3-0.9), median arterial BF velocity 1.5 (0.6-3.6) m/s, mean venous ID 7.6 +/- 2.2 mm, median venous RI 0.3 (0.3-0.9), mean venous BF velocity 1.6 +/- 0.7 m/s, and median venous BF volume 530 (120-1890) ml/min. Patients with poor functioning AVF had significantly less arterial ID, higher arterial RI, less venous ID, less venous BF velocity and volume. Duplex sonography findings obtained for clinically estimated well functioning shunt should be considered as normal Doppler values. Blood vessels' morphologic features depend upon age, and older patients have more pronounced changes.

Topics: Arteriovenous Shunt, Surgical; Blood Flow Velocity; Cross-Sectional Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Renal Dialysis; Thrombosis; Ultrasonography, Doppler, Duplex

Recombinant human erythropoietin (r-HuEPO) corrects cancer-related anemia and, thereby, improves quality of life. The purpose of the present study was to measure the impact of erythropoietin on hemoglobin and mood state in patients with metastatic breast cancer and mild anemia (Hgb < 12.0 g/dL). Women were randomized to receive usual care (G1) or usual care plus r-HuEPO (G2). Usual care included transfusions as necessary and fatigue education. R-HuEPO was begun at 40,000U subcutaneously per week. At 4 weeks, the dose was increased to 60,000U if Hgb had not increased > or = 1.0 g/dL. The drug was discontinued at 8 weeks if hemoglobin improvement was < 1.0 g/dL. The study was terminated early (n = 27, G1 = 13, G2 = 14) when 4/14 (28.5%) subjects in G2 developed thrombotic events (deep vein thrombosis [DVT] in 1; DVT plus pulmonary embolism [PE] in 1; DVT plus PE 1 month after drug discontinuation in 1; and brachial vein thrombosis with infected Mediport in 1). In all four patients, Hgb levels were normal at the time of the event. No patient in G1 developed a thrombotic event. There were no significant differences in demographic characteristics or current chemotherapy regimen in G1 vs. G2. The decision to terminate the trial was made after considerable deliberation. The increased incidence of thrombotic events in the r-HuEPO (G2) arm of this study exceeds that in prior studies in this population and prior r-HuEPO trials. This may relate to the administration of r-HuEPO in this high-risk population, but the small sample size and possible predisposing risk factors preclude definitive conclusions.

Topics: Anemia; Breast Neoplasms; Erythropoietin; Fatigue; Female; Humans; Middle Aged; Palliative Care; Quality of Life; Recombinant Proteins; Thrombosis; Treatment Outcome; Withholding Treatment

We reviewed clinical and molecular data of 23 consecutive unrelated patients affected by paroxysmal nocturnal hemoglobinuria (PNH) (19 with hemolytic PNH, 3 with aplastic anemia/PNH, and 1 with myelodysplasia/PNH syndrome) with a mean follow-up of 11.8 years. Five patients had thrombotic episodes, and 10 needed regular blood transfusions; 2 died for cerebral hemorrhage and kidney failure, and 2 spontaneously recovered from PNH. Twenty different PIG-A gene mutations were detected in 21/23 patients: 15 frameshift, 1 splicing, 2 nonsense, and 2 missense mutations. Two mutations (DelG341 and IVS2 +1g-a) were detected twice. A PIG-A mutated clone was also revealed in the two patients in complete clinical remission. One patient with aplastic anemia/PNH syndrome was treated with two courses of antilymphocyte globulin and cyclosporin with partial sustained response. Six patients were given rHu-EPO 150 U/kg/day s.c. for at least 6 months: one became transfusion-independent for 8 months and then discontinued treatment for clinical complications; one displayed a mean rise of Hb of 1.5 g/dL and is currently maintaining Hb levels higher than 9 g/dL after 54 months of therapy. Mutation specific quantitative-competitive PCR showed that the rise of hemoglobin was related to an increase of PIG-A negative molecules, suggesting that the efficacy of rHu-EPO therapy may be due to the stimulation of the abnormal clone.

Topics: Adolescent; Adult; Antilymphocyte Serum; Cyclosporine; DNA Mutational Analysis; Drug Monitoring; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Hemoglobinuria, Paroxysmal; Humans; Immunosuppression Therapy; Male; Membrane Proteins; Middle Aged; Mutation; Polymerase Chain Reaction; Recombinant Proteins; Thrombosis; Treatment Outcome

Some parameters of extrinsic coagulation pathway, including concentration and activity of tissue factor and concentration of tissue factor pathway inhibitor, have been estimated in uremic hemodialysis patients. The impact of erythropoietin treatment on the extrinsic coagulation pathway has also been the aim of the study. Increased concentration of tissue factor pathway inhibitor--TFPI has been found both in dialysed and non-dialysed uremic patients. This finding may be the evidence of endothelial damage as well as the protective factor against thrombotic complications. Erythropoietin treatment seemed not to induce statistically significant changes in extrinsic coagulation pathway. Some results indicate that estimation of "truncated' and "full length" forms of TFPI may be more useful comparing to complete TFPI concentration.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Erythropoietin; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Dialysis; Thromboplastin; Thrombosis; Treatment Outcome; Uremia

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

Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown.. One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation.. In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004).. Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

Topics: Adult; Aged; Anemia; Cardiac Volume; Cardiomyopathy, Dilated; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Patient Satisfaction; Quality of Life; Renal Dialysis; Surveys and Questionnaires; Thrombosis

Correction of uremic platelet serotonin (5-HT) storage pool deficiency is one of the very early hemostatic effects of erythropoietin (Epo) therapy. In this work, platelet 5-HT with relation to primary hemostasis was studied in 15 hemodialysis patients treated with Epo for 8 months. Moreover, effects of ketanserin, a blocker of platelet and vascular smooth muscle cell 5-HT2A receptors, in these patients were followed. The parameters studied were compared with relevant values in healthy controls and in hemodialysis patients not treated with Epo, and remeasured in the long-term Epo patients after a 14-day oral ketanserin trial. Platelet 5-HT content in the eighth month of Epo therapy was not different from the one in untreated patients. Ristocetin- and collagen-induced platelet aggregation were enhanced in comparison with both control groups, as opposed to unaltered response to ADP and arachidonic acid. Fibrinogen concentration was lower than in the untreated group. An inverse correlation between ADP-induced platelet aggregation and the skin bleeding time (r=-0.536, p<0.05) and a positive one between the former and platelet 5-HT (r=0.644, p<0.01) were found. Platelet count correlated positively with both platelet 5-HT (r=0.823, p<0.0002) and ADP-induced platelet aggregation (r=0.596, p<0.02). Ketanserin produced a decrease in ristocetin-induced platelet aggregation, fibrinogen, and prolongation of the bleeding time. The first two of the changes correlated positively with their pre-ketanserin values (r=0.923, p<0.00001 and r=0.839, p< 0.0001, respectively). Post-ketanserin, positive correlations between depressed ristocetin- and arachidonic acid-induced platelet aggregation (r=0.760, p<0.005), and between collagen- and corresponding values of arachidonic acid- (r=0.622, p<0.02), ADP-induced platelet aggregation (r=0.396, p<0.01), and platelet 5-HT (r=0.654, p<0.05) were found. Efficient hemostasis in hemodialysis patients on protracted Epo therapy is, in part, dependent on enhanced platelet aggregability. Correction of platelet 5-HT storage pool deficiency is not evident in this stage but 5-HT still influences complex mechanisms of primary hemostasis. Ketanserin is of anticoagulant value in these patients but its effects must be weighted against possible exacerbation of the anemia.

Topics: Adolescent; Adult; Bleeding Time; Blood Platelets; Child; Erythropoietin; Female; Fibrinogen; Hemostasis; Humans; Ketanserin; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Storage Pool Deficiency; Renal Dialysis; Serotonin; Thrombosis; Time Factors

A multicenter, double-blind, placebo-controlled, parallel-group study was undertaken to determine whether Epoetin alfa can reduce perioperative transfusion requirements. Twenty-six medical centers enrolled 316 patients who were scheduled for major orthopedic surgery and were expected to require > or = 2 units of blood. Patients were stratified according to baseline hemoglobin levels and randomly assigned to receive either Epoetin alfa (300 IU/kg or 100 IU/kg) or placebo for 15 consecutive days starting 10 days prior to, on the day of, and for 4 days after surgery. Epoetin alfa (300 IU/kg) resulted in significantly less exposure to allogeneic blood transfusion compared with placebo (16%) versus 45%) in patients whose baseline hemoglobin level was > 10 to < or = 13 g/dL (P = 0.024). Mean number of units transfused per patient was also lower among those treated with Epoetin alfa (overall, P = 0.027). Epoetin alfa was safe and well tolerated in this population.

Topics: Aged; Blood Loss, Surgical; Blood Transfusion; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobinometry; Hip; Humans; Intraoperative Period; Knee; Male; Middle Aged; Orthopedics; Postoperative Complications; Preoperative Care; Recombinant Proteins; Risk Factors; Thrombosis

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

Two hundred forty-four anemic hemodialysis patients were randomized into recombinant erythropoietin and placebo-treated groups during a 12-wk double-blind phase, followed by a 24-wk open-label period. Mean platelet count rose from the baseline value of 242 x 10(9)/L to 264 x 10(9)/L on day 5 of epoetin therapy (P < 0.001, paired t test). Mean platelet count peaked at 290 x 10(9)/L on day 40 and remained at a significantly elevated level below the peak thereafter. The peak platelet count did not exceed the normal range in a majority of cases. Platelet count was unaffected by placebo. Patients without an erythropoietic response during the first few weeks of therapy exhibited a rise in platelet count comparable to that in patients with a satisfactory erythropoiesis. Patients with low initial serum ferritin concentrations had baseline platelet counts comparable to those with normal or high ferritin values and showed a similar rise in platelet count during therapy. As a group, patients with baseline platelet counts above 400 x 10(9)/L showed no rise in platelet count, whereas those with normal or reduced platelet counts showed a marked thrombopoietic response to epoetin. Erythropoietin therapy did not significantly alter the incidence of blood access thrombosis when compared with placebo treatment.

Topics: Anemia; Catheters, Indwelling; Double-Blind Method; Erythropoietin; Female; Hematopoiesis; Humans; Immunologic Factors; Male; Middle Aged; Platelet Count; Recombinant Proteins; Regression Analysis; Renal Dialysis; Thrombosis

Recombinant human erythropoietin (rh-EPO) has been shown to be effective in the treatment of renal anemia. Additionally, rh-EPO improves the hemostatic defect of uremia. On the other hand, a hypertensinogen effect and an increased risk for thrombosis have been reported in hemodialysis (HD) patients with rh-EPO. 20 HD patients in Homburg were recruited for a multicenter, placebo-controlled study (MF 3981), aiming to assess the risk of rh-EPO. Initially, 10 patients received rh-EPO at a dose of 3 x 80 U/kg body weight and week which was subsequently adjusted according to the hematocrit. After 6 months, the patients receiving placebo were changed to rh-EPO therapy. Clinical and laboratory data were obtained before, as well as 1, 3, 6 and 12 months after beginning of the study. Erythrocyte counts increased significantly in the rh-EPO group. Also, an increase of platelet count, fibrinogen and plasma viscosity was observed during rh-EPO. Tissue type plasminogen activator and plasminogen activator inhibitor as well as von-Willebrand-factor remained unchanged, although a shortening of the bleeding time was observed. Blood pressure and arterial blood flow were not influenced by rh-EPO.

Topics: Blood Viscosity; Erythrocyte Count; Erythropoietin; Hematocrit; Humans; Hypertension, Renal; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Risk Factors; Thrombosis

Topics: Anemia; Arteriovenous Shunt, Surgical; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Multicenter Studies as Topic; Neoplasms; Renal Dialysis; Seizures; Thrombocytosis; Thrombosis

Topics: Adult; Aged; Anemia; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Random Allocation; Renal Dialysis; Reticulocytes; Thrombosis

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythrocyte Count; Erythropoietin; Female; Ferritins; Growth; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Multicenter Studies as Topic; Reticulocytes; Seizures; Thrombosis

To determine the effectiveness and safety of recombinant human erythropoietin (rHuEpo).. Hemodialysis patients (333) with uncomplicated anemia (hematocrit less than 0.30). All received rHuEpo intravenously, three times per week at 300 or 150 U/kg body weight, which was then reduced to 75 U/kg and adjusted to maintain the hematocrit at 0.35 +/- 0.03 (SD).. The baseline hematocrit (0.223 +/- 0.002) increased to 0.35, more than 0.06 over baseline within 12 weeks in 97.4% of patients. Erythrocyte transfusions (1030 within the 6 months before rHuEpo therapy) were eliminated in all patients within 2 months of therapy. Sixty-eight patients with iron overload had a 39% reduction in serum ferritin levels after 6 months of therapy. The median maintenance dose of rHuEpo was 75 U/kg, three times per week (range, 12.5 to 525 U/kg). Nonresponders had complicating causes for anemia, myelofibrosis, osteitis fibrosa, osteomyelitis, and acute or chronic blood loss. Adverse effects included myalgias, 5%; iron deficiency, 43%; increased blood pressure, 35%; and seizures, 5.4%. The creatinine, potassium, and phosphate levels increased slightly but significantly. The platelet count increased slightly but there was no increase in clotting of vascular accesses.. The anemia of hemodialysis patients is corrected by rHuEpo resulting in the elimination of transfusions, reduction in iron overload, and improved quality of life. Iron stores and blood pressure must be monitored and treated to maintain the effectiveness of rHuEpo and to minimize the threat of hypertensive encephalopathy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Erythropoietin; Female; Hematocrit; Humans; Iron Deficiencies; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Quality of Life; Recombinant Proteins; Thrombosis

Von Hippel-Lindau protein (VHL) is essential to hypoxic regulation of cellular processes. VHL promotes proteolytic clearance of hypoxia-inducible transcription factors (HIFs) that have been modified by oxygen-dependent HIF-prolyl hydroxylases. A homozygous loss-of-function VHL

Topics: Erythropoietin; Ferritins; Humans; Hypoxia; Iron Deficiencies; Polycythemia; Thrombosis; Transferrin; Von Hippel-Lindau Tumor Suppressor Protein

Discriminating polycythemia vera (PV) from secondary polycythemia (SP) is crucial due to the inherent risk of thrombosis in PV and different treatment approaches. The majority of PV patients have subnormal serum erythropoietin levels and harbor Janus kinase 2 (JAK2) mutations; however, serum erythropoietin levels may be normal in approximately one third of PV patients and mutational analysis is costly and requires access to specialized laboratories. Recently, neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) emerged as rapidly available biomarkers to identify PV patients under an increased risk of thrombosis and death. This multicenter retrospective study investigated whether these two biomarkers may also be used to differentiate PV from SP. A total of 207 subjects were included (103 PV and 104 SP) with both baseline NLR (median 4.33 vs. 1.89) and PLR (median 259.12 vs. 81.11) being significantly higher in PV than in SP (p < 0.001 for both analyses). According to the receiver operating curve analysis, PLR (area under the curve, AUC 0.936, the optimal cut-off value of > 138.1 had 82.5% sensitivity and 91.67% specificity for the detection of PV) outperformed other tested variables (NLR, total leukocytes, neutrophils, lymphocytes and platelets) and its cut-off values with 100% specificity and sensitivity were able to confirm (PLR > 224.56; 31% patients) and to exclude (PLR < 68.8; 13% patients) the highest proportions of PV patients. Therefore, PLR may represent a cheap and a rapidly available biomarker with valuable diagnostic and prognostic properties. This information may be particularly useful in resource-limited settings; however, our results need validation on larger datasets.

Topics: Biomarkers; Blood Platelets; Erythropoietin; Humans; Lymphocytes; Neutrophils; Platelet Count; Polycythemia; Polycythemia Vera; Prognosis; Retrospective Studies; Thrombosis

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function.\ \ Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice.\ \ Conclusions: Administration of roxadustat has no significant impact on platelet production and function.

Topics: Animals; Blood Coagulation; Blood Platelets; Case-Control Studies; Disease Models, Animal; Erythropoietin; Glycine; Hematinics; Humans; Isoquinolines; Male; Mice, Inbred C57BL; Platelet Activation; Renal Insufficiency, Chronic; Thrombopoiesis; Thrombosis

Anemia is one of severe complications in the perioperative period of total hip arthroplasty (THA). Erythropoietin (EPO) has been considered to improve patients' anemia state, but its efficiency and safety remains controversial.. A total of 152 patients who underwent total hip arthroplasty from January 2017 to March 2019 were randomized to 2 groups. Recombinant human erythropoietin (rHu-EPO) group was treated with rHu-EPO subcutaneous injection 10000 IU after operation and once daily in the next week, while control group was treated with none extra treatment. Routine hematologic examination and thrombelastography (TEG) performed at different time point respectively. Doppler ultrasound for bilateral lower limbs was performed 1 day before surgery and 7 days after surgery. Auxiliary examination outcomes, blood transfusions outcomes, and postoperative complications were recorded as assessment indicators.. The difference in the relevant indexes of traditional coagulation and TEG values between two groups were not significantly. No significant difference was observed in the incidence of thromboembolism events and other complications between two groups during postoperative period. The amount of intraoperative blood loss was similar between the two groups. However, the postoperative use and dosage of allogeneic blood in the rHu-EPO group were lower than those in the control group. The hemoglobin and hematocrit level in the rHu-EPO group were higher than that in the control group after surgery.. Postoperative subcutaneous injection of rHu-EPO can improve hematological anemia-related parameters, reduce the use and dosage of allogeneic blood transfusions (ABTs), and has no significant influence on the formation of thrombosis and other complications in patients undergoing total hip arthroplasty in short term.

Topics: Aged; Anemia; Arthroplasty, Replacement, Hip; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Perioperative Period; Postoperative Complications; Prospective Studies; Recombinant Proteins; Severity of Illness Index; Thrombelastography; Thrombosis

Topics: Erythropoietin; Hematocrit; Humans; Hypoxia; Polycythemia; Thrombosis

Stroke is associated with neuroinflammation, neuronal loss and blood-brain barrier (BBB) breakdown. Thus far, recombinant tissue-type plasminogen activator (rtPA), the only approved treatment for acute ischemic stroke, increases the risk of intracerebral hemorrhage and is poorly efficient in disaggregating platelet-rich thrombi. Therefore, the development of safer and more efficient therapies is highly awaited. Encouraging neuroprotective effects were reported in mouse models of ischemic stroke following administration of erythropoietin (EPO). However, previous preclinical studies did not investigate the effects of EPO in focal ischemic stroke induced by a platelet-rich thrombus and did not consider the implication of age. Here, we performed middle cerebral artery occlusion by inducing platelet-rich thrombus formation in chimeric 5- (i.e. young) and 20- (i.e. aged) months old C57BL/6 mice, in which hematopoietic stem cells carried the green fluorescent protein (GFP)-tag. Recombinant human EPO (rhEPO) was administered 24 hours post-occlusion and blood-circulating monocyte populations were studied by flow cytometry 3 hours post-rhEPO administration. Twenty-four hours following rhEPO treatment, neuronal loss and BBB integrity were assessed by quantification of Fluoro-Jade B (FJB)-positive cells and extravasated serum immunoglobulins G (IgG), respectively. Neuroinflammation was determined by quantifying infiltration of GFP-positive bone marrow-derived cells (BMDC) and recruitment of microglial cells into brain parenchyma, along with monocyte chemotactic protein-1 (MCP-1) brain protein levels. Here, rhEPO anti-inflammatory properties rescued ischemic injury by reducing neuronal loss and BBB breakdown in young animals, but not in aged littermates. Such age-dependent effects of rhEPO must therefore be taken into consideration in future studies aiming to develop new therapies for ischemic stroke.

Topics: Age Factors; Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Chemokine CCL2; Disease Models, Animal; Erythropoietin; Flow Cytometry; Green Fluorescent Proteins; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Cerebral Artery; Neuroprotective Agents; Recombinant Proteins; Stroke; Thrombosis

We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 high-dose group, but not in lower dose groups with a similar high HCT.

Topics: Animals; Cytokines; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Male; Polycythemia; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reticulocytes; Thrombosis

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Drug Evaluation; Epoetin Alfa; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Hematocrit; Humans; Hypertension; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Thrombosis

This study examined the safety, pharmacodynamic (PD), and pharmacokinetic (PK) biosimilarity of the human recombinant erythropoietin (EPO) products ior(®) EPOCIM and Eprex(®) following a 28-day repeated intravenous dose administration in male and female Sprague-Dawley rats with a 14-day recovery period. Safety profiling was based on clinical observations, clinical pathology, and pathology findings for control rats dosed with vehicle and rats dosed either with 30, 300, and 600 I.U./kg of ior(®) EPOCIM or 600 I.U. of Eprex(®) . Adverse findings for both ior(®) EPOCIM and Eprex(®) were similar and were a consequence of thrombotic events (ulcerative skin lesions, swollen hock joints/lameness, stomach ulcers) and decreased body weight gains, all known adverse reactions to this class of drug in rats. With the exception of stomach ulcers, all other adverse findings were fully reversible. Neither drug stimulated the production of antidrug antibodies. As expected, ior(®) EPOCIM and Eprex(®) both increased reticulocyte, red blood cell, hemoglobin, and hematocrit levels in rats. The PK of EPO following dosing with ior(®) EPOCIM was well behaved and consistent with the literature. The results of this study imply that ior(®) EPOCIM and Eprex(®) had safety profiles, PD responses, and toxicokinetic profiles that were biosimilar.

Topics: Administration, Intravenous; Animals; Biosimilar Pharmaceuticals; Chemistry, Pharmaceutical; Epoetin Alfa; Erythropoietin; Female; Hematinics; Male; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Therapeutic Equivalency; Thrombosis; Toxicokinetics; Weight Gain

Topics: Acute Coronary Syndrome; Adult; Diagnosis, Differential; Doping in Sports; Echocardiography; Electrocardiography; Erythropoietin; Heart Ventricles; Humans; Male; Thrombosis

Topics: Acute Coronary Syndrome; Doping in Sports; Erythropoietin; Heart Ventricles; Humans; Male; Thrombosis

Topics: Acute Coronary Syndrome; Doping in Sports; Erythropoietin; Heart Ventricles; Humans; Male; Thrombosis

Alternate erythropoietin (EPO)-mediated signaling via the heteromeric receptor composed of the EPO receptor and the β-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha-mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue components. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.

Topics: Animals; Burns; Cell Line; Erythropoietin; Inflammation; Male; Mice; Mice, Inbred C57BL; Microvessels; Signal Transduction; Skin; Thrombosis; Tumor Necrosis Factor-alpha; Wound Healing

Calvarial remodeling is typically associated with significant blood loss. Although preoperative erythropoiesis-stimulating agents have proven to significantly decrease the need for blood transfusions, recent data in adults have raised concerns that elevating hemoglobin levels greater than 12.5 g/dl may increase the risk of thrombotic events. This study was designed to assess the risks of erythropoietin in the pediatric population.. Records were retrospectively reviewed from 2000 to 2008 at three major metropolitan children's hospitals of all children undergoing calvarial remodeling after receiving preoperative erythropoietin. Demographic and perioperative outcome data were reviewed, including transfusion reactions, pressure ulcer secondary to prolonged positioning, pneumonia, infection, deep vein thrombosis, cerebrovascular accident, pulmonary embolism, sagittal sinus thrombosis, pure red cell aplasia, and myocardial infarction.. A total of 369 patients met the inclusion criteria (mean age, 0.86±1.1 years). On average, three preoperative doses of erythropoietin were administered (600 U/kg). Iron was also supplemented. No complications associated with dosing were noted, there were no thrombotic events identified, and no other major complications were seen (i.e., death or blindness). Thirty-one patients (8.40 percent) experienced one or more postoperative complications. There was no significant correlation between hemoglobin levels greater than 12.5 g/dl and the occurrence of any noted complication.. With zero thrombotic postoperative complications, the authors estimate the risk of a thrombotic event in the pediatric population to be less than 0.81 percent (95 percent confidence). These data suggest that preoperative administration of erythropoietin in children undergoing calvarial remodeling does not appear to increase the incidence of thrombotic events or other significant complications.. Therapeutic, IV.

Topics: Blood Loss, Surgical; Erythropoietin; Female; Hematinics; Humans; Infant; Male; Orthopedic Procedures; Postoperative Complications; Preoperative Care; Retrospective Studies; Skull; Synostosis; Thrombosis; Treatment Outcome

The authors evaluated the patterns of use and the risk of thromboembolic events (TEE) associated with erythropoietin-stimulating agents (ESAs) in older patients with metastatic breast cancer who were receiving chemotherapy.. The study was retrospective and used the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995-2005, treated with chemotherapy, ≥66 years old, with full coverage of Medicare A and B were included. The World Health Organization's International Classification of Diseases (ICD-9) and the Healthcare Common Procedure Coding System (HCPCS) were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression.. Of 2266 women, 980 (43.3%) received ESAs, and 1286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines, or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, P = .031); deep-vein thrombosis (DVT; 21.3% vs 14.4%, P<.001), other/unspecified thromboembolic event (TEE; 19.8% vs 14.7%, P = .001), and any clot (31.3% vs 23.4%, P<.0001). In multivariate analysis, patients receiving ESAs had increased risk for DVT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.75), and any clot (OR, 1.26; 95% CI, 1.02-1.57). A dose-dependent effect was evident for stroke, DVT, other TEE, and any clot.. In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE, and any clot. The data show that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore, caution is recommended when using these agents.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Humans; Medicare; Neoplasm Metastasis; Retrospective Studies; SEER Program; Stroke; Thrombosis; United States; Venous Thrombosis

Topics: Blood Pressure; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Stents; Thrombosis

Traditionally, erythropoietin (EPO) is described as a hematopoietic cytokine, regulating proliferation and differentiation and survival of the erythroid progenitors. The recent finding of new sites of EPO production and the wide spread distribution of EPO receptors (EPO-R) on endothelial cells, cardiomyocytes, renal cells as well as the central and peripheral nervous system raised the possibility that EPO may exert pleiotropic actions on several targets. Indeed studies (mainly preclinical) have documented protective, non-hematopoietic, abilities of EPO in a variety of tissue. However, the data obtained from clinical studies are more skeptical about these properties. This article provides a comprehensive overview of EPO and its derivatives.

Topics: Anemia; Cardiotonic Agents; Cytoprotection; Erythropoietin; Hypertension; Kidney; Neoplasms; Neuroprotective Agents; Receptors, Erythropoietin; Thrombosis

Although microsurgery has rapid expanded, problems related to microarterial anastomosis continue. Cigarette smoking is one of the major risks for anastomosis by increasing platelet adhesion, and its effects on endothelial cells. Aim of this article is to study the negative effects of cigarettes on microarterial anastomosis line, and to investigate the protective effects of recombinant human erythropoietin (rHuEPO).Ninety-six Sprague-Dawley male rats were divided into 3 groups: group 1 was the control. Rats in groups 2 and 3 were exposed to cigarette smoke starting 21 days prior to surgery for 3 times a day. In group 3, additional 150 IU/kg rHuEPO was given via subcutaneously every 48 hours after microvascular anastomosis, femoral arterial samples, and blood samples were taken for assessment at 1st, 3rd, 5th, and 7th day. Intimae/media ratios were calculated for morphologic analyses.On morphologic analysis of femoral arteries there were statistically significant differences for all 3 groups at 1st, 3rd, 5th, and 7th days (P < 0, 05). The group that made differences was group 2, according to one-way analysis of variance within 3 groups in all days.Smoking decreases endothelial cells healing and causes more thromboses. rHuEPO can prevent these negative effects of smoking.

Topics: Anastomosis, Surgical; Animals; Arterioles; Endothelial Cells; Erythropoietin; Femoral Artery; Injections, Subcutaneous; Male; Microsurgery; Postoperative Complications; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Factors; Smoking; Thrombosis

To determine if levels of coated-platelets, which are potentially pro-thrombotic, are increased in end-stage renal disease patients on haemodialysis, a condition associated with high cardiovascular disease risk.. In a cross-sectional observational study, coated-platelet levels were measured by flow cytometry in 25 end-stage renal failure haemodialysis patients and 25 controls without renal disease. Associations between coated-platelet levels and clinical and biochemical factors relevant to renal and cardiovascular disease were evaluated.. Mean +/- SD coated-platelet levels were higher in the dialysis group than in the control group (39.3+/-14.3% vs 30.9+/-10.3%, P=0.02). The number of subjects with high coated-platelet levels (>40%) was larger in the dialysis than in the control group (13/25 vs 4/25, chi(2) test, P=0.007). On univariate analysis, coated-platelet levels correlated with serum C-reactive protein levels in renal failure (r=0.47, P=0.02) and inversely with white cell count in the control group (r= -0.60, P=0.001). Coated-platelet levels were higher in dialysis patients reporting alcohol abstinence than among those reporting 'social' drinking (44.3+/-12.6 vs 28.8+/-13.5%, P=0.01). Age, gender, body weight, smoking, diabetes, lipid levels and lipid-lowering drugs were not associated with coated-platelet levels (all P>0.05).. Coated-platelet levels are increased in haemodialysis patients relative to subjects with normal renal function, and are related to inflammation and alcohol abstinence. Other vascular risk factors, such as smoking, lipids and diabetes, were not related to coated-platelet levels. Coated-platelets may be implicated in the increased thrombosis and vascular risk in end-stage renal disease.

Topics: Aged; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Count; Renal Dialysis; Thrombosis

No data exists that directly compares hemoglobin and hematocrit levels between cancer patients with and without occurrence of thrombosis during treatment with erythropoiesis stimulating agents (ESAs).. To determine the association of hemoglobin and hematocrit levels with the occurrence of thrombosis in cancer patients treated with ESAs.. A retrospective case-control study approved by the Institutional Review Board was conducted on cancer patients billed for epoetin or darbepoetin between 1 July 2002 and 30 June 2007. Cases were defined as patients billed for thrombosis while controls were defined as patients not billed for thrombosis.. Sixteen patients had an occurrence of thrombosis (cases) and were matched to 16 patients that did not have an occurrence of thrombosis (controls) based on age, sex, and cancer type. The mean peak hemoglobin levels for cases and controls were 12.6 +/- 1.2 g/dL versus 12.6 +/- 1.4 g/dL (p = 0.9). The mean peak hematocrit levels for cases and controls were 37.3 +/- 3.8% versus 37.9 +/- 4.3% (p = 0.8). For the 16/586 (2.7%) patients with thrombosis, the mean hemoglobin and hematocrit at time of thrombosis were 9.6 +/- 1.0 g/dL and 28.9 +/- 3.1%. A significant identifiable risk factor for thrombosis between the cases and controls was history of thrombosis 31.3% versus 0% (p = 0.04).. There was no statistical difference in peak hemoglobin and hematocrit levels between patients with thrombosis and those without thrombosis. Further study is warranted to determine if these levels are true risk factors for thrombosis.

Topics: Anemia; Anticoagulants; Case-Control Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Recombinant Proteins; Retrospective Studies; Risk Factors; Thrombosis; Time Factors

Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Aim of our study was to evaluate the impact of a maximised 7 day-combination therapy with G-CSF plus EPO on the healing process following balloon injury of the rat carotid artery.. Osmotic pumps to systemically deliver G-CSF and EPO at saturating doses during the first seven days post injury were implanted into the peritoneal cavity of splenectomised male Sprague-Dawley rats. Cytokine treatment resulted in significantly elevated numbers of white blood cells, hematocrit levels, circulating hematopoietic stem cells, and-temporarily-circulating endothelial precursors. Functional reendothelialisation as assessed by Evan's blue staining on day 14 post injury was not affected by the cytokine treatment. The neointimal response was analysed on day 7 and 28 post injury, and was significantly higher at the day 7 timepoint (Cytokines: I/M-ratio 1.10+/-0.09 vs. Saline: 0.36+/-0.06). Cytokine treated rats also displayed higher rates of thrombotic occlusion (Cytokines: 25-33% vs. Saline: 0%). Serum levels of PAI-1, TGFbeta1, and PDGF-BB were not elevated in the cytokine treated rats. The proliferative rates both in the injured vessel wall and the surrounding adventitia as assessed by BrdU incorporation were significantly higher in the cytokine treated animals. The number of CD45(pos) hematopoietic cells was significantly higher in the adventitia of the cytokine treated rats. Vasa vasorum were not found to be significantly different. The increased neointimal response was not due to expression of G-CSF- or EPO-receptors on VSMCs within the vessel wall or myofibroblasts in the adventitia.. The systemic administration of G-CSF plus EPO during the first week after balloon-injury impairs the vascular healing process by increasing the neointimal response and the risk for thrombotic occlusion.

Topics: Animals; Becaplermin; Carotid Artery Injuries; Catheterization; Disease Models, Animal; Drug Therapy, Combination; Endothelial Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hyperplasia; Immunohistochemistry; Leukocyte Common Antigens; Male; Plasminogen Activator Inhibitor 1; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Thrombosis; Transforming Growth Factor beta1; Tunica Intima; Wound Healing

Erythropoietin has been shown to shorten survival in cancer patients under certain circumstances. Possible mechanisms are an increase in thrombotic events, tumour progression, and induction of angiogenesis. The FDA advises its use in oncology only as a replacement for blood transfusions in patients receiving chemotherapy. In these patients, a rise in haemoglobin above 7.4 mmol/l should be avoided.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Humans; Neoplasms; Neovascularization, Pathologic; Survival Analysis; Thrombosis; Treatment Outcome

Erythropoietin (EPO) treatment has become the standard treatment of renal anemia. Though a link between hematopoiesis-stimulating drugs and thrombosis has not been proven, it is generally assumed that systemic application of EPO and its analogues increases the risk for thrombotic events.. Here we show in C57BL/6J mice that 4-week treatment with the long-lasting EPO analogue darbepoetin-alpha (DPO) at a dose of 10 microg/kg/week induces a reduction of platelet reactivity using flow cytometry and Western blot analysis of tyrosine-specific platelet phosphorylation. Additionally, immunohistochemistry of endothelial adhesion molecule expression and ELISA of circulating endothelial activation markers demonstrated a reduced endothelial activation. Immunohistochemistry and RT-PCR analysis revealed a significant (P<0.05) increase of eNOS expression. Further, DPO did not exert prothrombogenic effects in a murine intravital microscopic thrombosis model of the cremaster muscle. The role of eNOS in prevention of DPO-mediated microvascular thrombosis is further underlined by a significantly accelerated thrombus formation on DPO treatment in eNOS (-/-) mice.. Thus, DPO-related erythropoiesis with a raised hematocrit is not associated with an increased risk for thrombosis as long as endothelial NO production serves as compensatory mechanism.

Topics: Anemia; Animals; Blood Platelets; Blotting, Western; Capillaries; Darbepoetin alfa; Disease Models, Animal; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Flow Cytometry; Gene Expression; Hematinics; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; P-Selectin; Prognosis; RNA; Thrombelastography; Thrombosis

Topics: Critical Illness; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Thrombosis; Wounds and Injuries

Thrombotic events are infrequently observed in erythropoietin treatments for the anemia in tumorous patients with chemotherapy. The manufacturers call attention to this possible side effect of all kind of such drugs.. To estimate the amount of thrombotic events in erythropoietin administrations during epoetin treatments for ovarian cancer patients treated with antineoplastic drugs.. 275 ovarian cancer patients were treated with erythropoietin in the Gynecologic Department at the National Institute of Oncology, Budapest, in the period between 2000 and 2006: 52 of them were given epoetin-alfa, 157 of them epoetin-beta and 66 of the patients received darbepoetin-alfa. Median age of the patients was 60 (ranges 22 and 84) years.. Thrombotic events were detected in 3 patients out of the 275: one with epoetin-alfa and two times with epoetin-beta treatment (3/275 = 1,1%). No definite causal relationship was confirmed between the thrombotic events and the erythropoietin drugs.. Thrombosis was infrequently monitored among the authors' patients similarly to the literature data.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Humans; Hungary; Incidence; Middle Aged; Ovarian Neoplasms; Recombinant Proteins; Retrospective Studies; Thrombosis

We had previously reported an association between the use of recombinant human erythropoietin (rHuEPO) and thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy and radiation. We hypothesized that low-dose warfarin would be effective prevention for thromboembolic events in this setting.. A retrospective analysis of patients with cervical or vulvo-vaginal carcinoma receiving chemoradiation and rHuEpo was performed. Thirty-two patients received rHuEpo alone, and 24 received warfarin (1-2 mg) and rHuEpo. The primary endpoint was objectively proven symptomatic venous thrombosis.. There was no difference in the baseline characteristics (e.g. age, stage, body mass index, mean and peak hemoglobin, WBC and platelet counts, and number of transfusions) between these two groups. The rate of thrombosis also was not statistically different (P = 0.62). Nine of 24 patients had a symptomatic deep vein thrombosis (DVT) while receiving warfarin compared to 10 of 32 patients not on warfarin. There was no difference between the two groups in the percentage of patients with upper extremity DVT (P = 0.83) or lower extremity DVT (P = 0.64).. Daily low-dose warfarin did not alter the incidence of symptomatic DVT in patients with cervical or vulvo-vaginal cancer who received rHuEpo in conjunction with chemoradiation.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Erythropoietin; Female; Genital Neoplasms, Female; Humans; Middle Aged; Recombinant Proteins; Retrospective Studies; Thrombosis; Uterine Cervical Neoplasms; Vaginal Neoplasms; Vulvar Neoplasms; Warfarin

Fistula thrombosis in patients on maintenance hemodialysis is an important morbidity factor. Arterial or venous thrombotic events have been described as complications in patients on regular hemodialysis. This study was designed to evaluate the risk factors for arteriovenous fistula thrombosis.. One hundred and seventy-one patients with arteriovenous fistula on maintenance hemodialysis were studied prospectively during a period of 14 months for any episode of arteriovenous fistula thrombosis, after anticardiolipin antibodies were assayed by ELISA. Other risk factors for thrombosis such as the presence of diabetes or hypertension, the use of erythropoietin (rhEPO), fistula site, gender, age, ultrafiltration, hypotension during dialysis, and the number of dialysis visits in a week were assessed.. Fifty-six percent of patients had IgG-anticardiolipin antibodies > or = 10GPL, which was significantly correlated with dialysis duration (23.18 +/- 24.56 months in patients with anticardiolipin antibodies < or = 10GPL vs. 37.73 +/- 36.35 months in patients with 20 < or = IgG-anticardiolipin antibodies < 40GPL). Within the 14 months of follow-up, 36 episodes of arteriovenous fistula thrombosis occurred in 31 patients (18.1%). Considering anticardiolipin antibodies and other risk factors in a Cox proportional hazard model, only fistula site (P = 0.021, RR = 2.48, Cl = 1.14 - 5.37) and erythropoietin (Eprex) use (P = 0.021, RR = 10.92, Cl = 1.43 - 83.02) seemed to have an influence on fistula patency. According to fistula site, the survival of brachiocephalic fistulas were significantly (P = 0.007) better than radiocephalic ones (1- and 3-year survival were 95% and 87% for upper, and 88% and 72% for lower ones, respectively).. Although the incidence of the anticardiolipin antibody was high in our patients, in the presence of other risk factors for thrombosis, we found no correlation between IgG-anticardiolipin antibodies and arteriovenous fistula thrombosis. Instead, erythropoietin (Eprex) use and fistula site seem to have an important role in the correlation between IgG-anticardiolipin antibodies and arteriovenous fistula thrombosis.

Topics: Antibodies, Anticardiolipin; Arteriovenous Shunt, Surgical; Catheters, Indwelling; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Renal Dialysis; Risk Factors; Survival Analysis; Thrombosis

Topics: Aged; Anemia; Anticoagulants; Diagnosis, Differential; Erythropoietin; Granulomatosis with Polyangiitis; Humans; Leg Ulcer; Male; Recombinant Proteins; Renal Insufficiency; Thrombosis; Treatment Outcome; Warfarin

Although unfractionated heparin is the most commonly used anticoagulant for hemodialysis and has been associated with bleeding episodes, a more devastating complication that can occur is heparin-induced thrombocytopenia (HIT). It is believed that HIT type II is much more dangerous than type I, because HIT type II is associated with thromboembolic complications whereas there are no such complications in HIT type I. However, increased clot formation in the extracorporeal circuit during hemodialysis with unfractionated heparin is sometimes experienced by not only patients with HIT type II but also those with HIT type I. Three patients with HIT type I are presented who suffered from clot formation during hemodialysis, and in whom 81 mg of aspirin and/or cessation of heparin was prescribed. All three patients had received recombinant human erythropoietin (rHuEpo). Both heparin and rHuEpo induce enhanced platelet aggregation; therefore, it is possible that even HIT type I patients may suffer clot formation in the extracorporeal circuit due to platelet activation via the synergistic effects of unfractionated heparin and rHuEpo.

Topics: Aged; Drug Synergism; Erythropoietin; Female; Heparin; Humans; Male; Middle Aged; Platelet Aggregation; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombosis

Polycythemia vera (PV) is a malignant disorder of hemaopoietic stem cells which is characterized by clonal hyperproliferation and a low rate of apoptosis. This study was to assess endogenous erythroid colony (EEC) formation in the bone marrow of PV patients and determine its clinical significance.. The bone marrow mononuclear cells of 26 patients with PV, 2 patients with secondary erythrocytosis (SE), and 19 normal controls were cultured by Marsh's method for EEC evaluation, and the clinical significance was evaluated.. EECs appeared in 25 patients with PV but not in 2 patients with SE and 19 normal controls. The number of EECs and the EEC ratio [EEC/erythropoietin (EPO)-dependent colony forming unit-erythroid (CFU-E)] in PV patients positively correlated with hemoglobin (Hb) levels. Their EEC number did not correlate with white blood cell (WBC) counts, platelet (PLT) counts, or leukocyte alkaline phosphatase (LAP) scores. Their EEC did not correlate with serum EPO levels. Fifteen patients with PV were treated with hydroxyurea (Hu) and/or interferon-alpha (IFN-alpha). Their EEC ratio before treatment positively correlated with the treatment time required for complete remission (CR) and negatively correlated with the time before relapse. The EEC numbers of 7 PV patients treated with Hu/IFN-alpha decreased after the blood cell counts dropped to normal levels. There was a positive correlation between the EEC ratio and the incidence of attacks of vascular thrombosis in PV patients. The numbers of apoptosised bone marrow mononuclear cells in PV patients were lower than those in normal controls. The EEC numbers of PV patients negatively correlated with the rate of apoptosis of bone marrow mononuclear cells.. EEC formation is characteristic in PV patients. EEC number in PV patients positively correlates with Hb levels, the time required for CR, and the incidence of attacks of vascular thrombosis. EEC number negatively correlates with the time before relapse. Bone marrow suppressive treatment might decrease EEC number. Thus, EEC number is a sensitive and specific parameter reflecting the abnormal hematopoietic clone burden induced by polycythemia vera. EEC number is an important diagnostic parameter for PV patients.

Topics: Adult; Aged; Apoptosis; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Polycythemia Vera; Thrombosis

Chronic inflammation is a major cause of morbidity and mortality in end-stage renal disease. The associated anemia in these patients due to renal cortical atrophy and erythropoietin deficiency is treated with recombinant erythropoietin. Recent reports suggest a growing incidence of symptomatic venous thrombosis in cancer patients treated with recombinant erythropoietin. Several investigators have reported on different mechanisms of thrombosis in these patients. We hypothesize that thrombosis in patients with end-stage renal disease due to increased expression of C-reactive protein (CRP) as a result of chronic inflammation promotes the release of thrombin activatable fibrinolytic inhibitor causing fibrinolytic deficit and eventually thrombosis. Furthermore, because endothelial nitric oxide is responsible for the maintenance of the normal vascular function, the decreased levels of nitric oxide in chronic inflammation cause endothelial damage and result in thrombosis. To test this hypothesis, blood samples were collected from 106 patients (49 male and 57 female, aged 59.8+/-15.7 years) with end-stage renal disease undergoing hemodialysis and treated with recombinant erythropoietin at a mean dose of 201.8 U/kg/week. Blood samples were drawn in 5-mL tubes containing 3.2% sodium citrate just before the hemodialysis procedure. These blood samples were immediately centrifuged to obtain platelet-poor plasma, which was aliquoted and frozen at -70 degrees C until further analysis. Erytropoietin antibodies were measured using an anti-EPO enzyme-linked immunosorbent assay (ELISA) method developed in our laboratory. Nitric oxide was measured using a NO analyzer (Sievers 280I, Ionics, Boulder, CO). Plasma CRP levels were measured with a highly sensitive ELISA method IMUNOCLONE CRP ELISA (American Diagnostica, Greenwich, CT). TAFI antigen levels in plasma were analyzed with an IMUCLONE TAFI ELISA kit (American Diagnostica, Greenwich, CT). TAFI functional activity was assayed with an ACTICHROME TAFI activity kit. The measured levels of nitric oxide, CRP, TAFI antigen, and TAFI functional were 37.36+/-36.8 (normal value, 37.49+/-18.96; range, 19.3-102 microM), 12.27+/-10.6 (normal value, < 1 microg/mL), 146.9+/-28.4% NHP (normal, 100% NHP), and 102.55+/-37% NHP (normal range, 22.3-165.7; mean, 89.5% NHP), respectively. The erythropoietin antibody was detected in 9.4% of the patient group. While 20% of the erythropoietin antibody-positive and 27.1% of the erythropoietin ant

Topics: Adult; Aged; Aged, 80 and over; Anemia; Autoantibodies; C-Reactive Protein; Carboxypeptidase B2; Chronic Disease; Complement Activation; Cytokines; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Induction; Erythropoietin; Female; Fibrinolysis; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Recombinant Proteins; Renal Dialysis; Thrombin; Thrombophilia; Thrombosis

Among 199 patients treated with thalidomide for multiple myeloma, four thromboses occurred in 49 cases during erythropoietin therapy (prevalence 8.1%; annual rate 7.25%), and another 14 events occurred in patients not on erythropoietin (9.3%; 7.56%). Thus, erythropoietin would seem not to increase the risk of thrombosis of myeloma patients receiving thalidomide.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antineoplastic Agents; Drug Synergism; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Risk; Thalidomide; Thrombosis; Venous Thrombosis; Warfarin

Vascular access failure is the main cause of morbidity in hemodialysis. Venous stenosis and subsequent thrombosis, as the result of intimal hyperplasia, is the major cause of vascular access failure. Intimal hyperplasia of the arteriovenous fistula (AVF) closely resembles the main histopathologic feature of atherosclerosis. In addition to the classic atherogenic risk factors, recently, cytomegalovirus (CMV) infection and parathyroid hormone (PTH) have been suggested as a potential cause of vascular disease.. In the present study, we evaluated the relationship between AVF dysfunction and mean plasma PTH, cholesterolemia, high titer anti-CMV immunoglobulin G (IgG) (>250 U/mL), hematocrit, and mean erythropoietin (EPO) dose in 36 cases and 51 controls matched for age, time on dialysis, and type of AVF.. A higher percentage of patients with AVF failure had a smoking habit and presented high anti-CMV IgG titer. Patients with AVF failure had significantly higher mean plasma PTH, whereas the groups did not differ for mean cholesterolemia and hematocrit. Mean EPO dose was slightly, but significantly, higher in the AVF failure group. Multiple logistic regression revealed that smoking, EPO dose, elevated mean plasma PTH and high titer anti-CMV antibodies, significantly increased the risk of AVF dysfunction.. Our data suggest that hyperparathyroidism, smoking habits, CMV infection and EPO, independently of the hematocrit achieved, represent independent risk factors for hemodialysis access thrombosis.

Topics: Aged; Arteriovenous Shunt, Surgical; Cytomegalovirus Infections; Erythropoietin; Female; Graft Occlusion, Vascular; Hematocrit; Humans; Hyperparathyroidism; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Risk Factors; Smoking; Thrombosis

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

Maintenance hemodialysis (HD) patients were studied to assess the effect on hemoglobin (Hb) concentration induced by the cyclic variation in hydration status.. Forty-nine HD patients were examined in three consecutive HD sessions in a 1-week treatment period. In a subgroup of 23 patients, Hb levels also were investigated during the long interdialytic interval.. Hb levels at the end of the long interdialytic interval were significantly lower by 0.5 to 0.6 g/dL (5 to 6 g/L) than those at the end of short intervals. Among all pre-HD and post-HD Hb values, levels measured at the end of short intervals were closest to the mean Hb value of the week, derived from calculation of the area under the curve (12.0 +/- 0.2 g/dL [120 +/- 2 g/L]). Intradialytic Hb increments were different in the three sessions (+1.6 +/- 0.1 g/dL [+16 +/- 1 g/L] after the long interval, +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] and +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] after short intervals [P < 0.001] and proportionate to weight loss [-3.4 +/- 0.1, -2.7 +/- 0.1, and -2.6 +/- 0.1 kg, respectively; P < 0.001]). Hb level increment and weight loss correlated directly (r = 0.527; P < 0.0001); each 1 L of ultrafiltration (UF) led to an increase in Hb level of approximately 0.4 g/dL (4 g/L). Plasma refilling accounted for an approximately 45% decrement in the intradialytic increase in Hb level 2 hours post-HD.. This study suggests that: (1) the end of the short interdialytic period is the most appropriate timing for anemia assessment, and (2) the remarkable hemodiluting effect of post-HD plasma refilling protects against excessive increments in Hb levels induced by UF.

Topics: Body Water; Drug Administration Schedule; Erythrocyte Indices; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thrombosis; Time Factors; Urination

Recombinant human erythropoietin (rHuEPO) administration has been associated with an increased risk of hypertension and thrombosis in uremic patients. rHuEPO and endothelial cells cultured in an uremic environment. Results indicate that rHuEPO does not exert an additional activating effect to that caused by the uremic media per se.

Topics: Cell Line; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Humans; Thrombosis; Uremia

We demonstrate that exposure of cultured human endothelial cells to rHuEPO resulted in a dose-dependent increase in the tyrosine kinase activity, with phosphorylation of JAK-2 followed by rapid phosphorylation of STAT-5. Simultaneously, rHuEPO induced long-lasting phosphorylation of MAPK p42/44. Activation of this signaling pathways was directly associated with an increase in the thrombogenic properties of the extracellular matrix generated by these cells, when they were exposed to flowing blood. The enhancement in the reactivity of the resulting extracellular matrix towards platelets was associated with a higher expression of tissue factor. All these effects were blocked by an antibody to the EPO receptor and by specific inhibitors of tyrosine phosphorylation. The observed action of rHuEPO on endothelial cells seemed to be specifically triggered by the subsequent events that follow receptor binding, and occurred even at pharmacological concentrations of the cytokine. Our results indicate that rHuEPO has a direct action on the endothelium, increasing the reactivity of the underlying extracellular matrix towards platelets, effect that may be attributed to an increase in the expression of TF.

Topics: Blood Platelets; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Extracellular Matrix; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Perfusion; Phosphorylation; Thromboplastin; Thrombosis; Umbilical Veins; von Willebrand Factor

Clinical experience indicates that bleeding and thrombotic tendencies co-exist in uremic patients. Numerous studies have shown that platelet functional defects contribute to the bleeding tendency in uremic patients. In contrast, there are no solid studies clarifying the pathogenesis of the prothrombotic state in uremic patients. Platelet-derived microparticles (PMPs), which are small vesicles with procoagulant activity released from activated platelets, are thought to be involved in clinical thrombogenesis. This study addressed the question of why uremic patients are thrombophilic even though they have a bleeding tendency, focusing on the clinical significance of PMPs.. The subjects were pre-dialyzed patients, patients under hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) therapy, and age-matched healthy controls. Analyses of PMPs were performed using a flow cytometer. Annexin V was used to probe procoagulant activity of PMPs. The impacts of the HD procedure, arteriovenous (AV) fistula, and recombinant human erythropoietin (rHuEPO) treatment on the release of PMPs were additionally assessed.. Major results are: (1) PMP counts were significantly greater in each uremic group than in controls. The PMP counts were not different among three types of uremic groups; (2) PMP counts were significantly higher in uremic patients with thrombotic events than in those without thrombotic events; and (3) the HD procedure and existence of AV fistula did not affect PMP counts, but rHuEPO treatment possibly enhanced the PMP release in these patients.. Elevated PMP counts may trigger thrombosis in uremic patients. The primary cause of PMP elevation in uremia was not clarified in this study.

Topics: Aged; Arteriovenous Shunt, Surgical; Blood Coagulation; Blood Platelets; Erythropoietin; Flow Cytometry; Humans; Middle Aged; Particle Size; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Thrombosis; Uremia

Recombinant human erythropoietin (rHuEPO) is considered to be a mitogenic and chemotactic agent in cultured endothelial cells (ECs). The effect of recombinant granulocyte-macrophage (rGM-CSF) and granulocyte (rG-CSF) colony-stimulating factors on the proliferation of human umbilical vein endothelial cells (HUVECs) has been controversial.. HUVEC proliferation and the release of endothelial markers in HUVEC culture stimulated by rHuEPO, rGM-CSF and G-CSF were measured.. We found the dose-dependent stimulating effect of rHuEPO and rGM-CSF on HUVEC proliferation, but we did not achieve this with rG-CSF. rHuEPO like rG-CSF was an effective agent in stimulating the plasminogen activator inhibitor (PAI)-1 release from HUVECs to a cultured medium, while rGM-CSF failed.. We suggest that rHuEPO showed prothrombotic changes in HUVEC culture. Our results support the idea of suspected rHuEPO direct prothrombotic role in haemodialysed patients treated with rHuEPO.

Topics: Biomarkers; Cell Division; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Plasminogen Activator Inhibitor 1; Recombinant Proteins; Thrombosis; Umbilical Veins

Are occurrences of vascular access thrombosis and hospitalization higher in hemodialysis patients with hematocrits (Hcts) > 36% compared to those < 36%? This 12-month retrospective study included 30 male hemodialysis patients who received erythropoietin (rHuEPO) for at least 6 months. Sixty percent (n = 18) had arteriovenous fistulas and 40% (n = 12) had polytetrafluoroethylene grafts. The mean age was 59.6 years. Twenty patients during 216 patient months had a mean Hct < 36% with five thromboses (2.3%). Ten patients during 118 patient months had a mean Hct > 36% with four thromboses (3.4%). There was no statistically significant difference between the thrombosis rates in the two groups. There were four hospitalizations in 118 patient months in the > 36% group (3.4%). There were 33 hospitalizations in 216 patient months in the < 36% group (15.3%). This is 4.5 times higher than the > 36% group. Our data suggest that Hcts > 36% are not associated with increased thrombosis and are associated with lower hospitalization rates.

Topics: Adult; Aged; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; Equipment Failure; Erythropoietin; Graft Occlusion, Vascular; Hematocrit; Hospitalization; Hospitals, Veterans; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polytetrafluoroethylene; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Factors; Tennessee; Thrombosis; Vascular Patency

So far it is not clear how erythropoietin affects the anticoagulant properties of vascular endothelium in uremia. Since serotonin is also thought to play a role in the pathogenesis of thrombosis, the aim of the study was to evaluate major components of extrinsic coagulation pathway, markers of endothelial cell injury, lipoprotein (a) and peripheral serotonergic mechanisms during rHuEPO therapy in hemodialyzed patients. The study was performed on chronically hemodialyzed patients divided into two groups: with rHuEPO treatment and without rHuEPO therapy in relation to the control group. In uremic patients, thrombomodulin and von Willebrand factor, activity of factor VII, tissue factor pathway inhibitor (TFPI) activity, TFPI and tissue factor (TF) concentrations, lipoprotein (a) level were significantly higher when compared to healthy volunteers. Treatment with rHuEPO resulted in a further significant rise in markers of endothelial cell injury: thrombomodulin and von Willebrand factor and TFPI concentration. Extrinsic coagulation factors: activities of factor VII and X, TFPI activity and TF activity and concentration, lipoprotein (a) and vitronectin remained unchanged during rHuEPO therapy. Platelet serotonin content and whole blood serotonin were significantly lower in uremic patients relative to healthy volunteers and during rHuEPO treatment they increased significantly. Whole blood serotonin reached normal values. Plasma serotonin, significantly elevated in uremia, did not change during rHuEPO therapy. Serotonin uptake by uremic platelets was significantly impaired and remained unaltered during rHuEPO administration. Serotonin release by uremic platelets was also significantly depressed but a significant improvement was observed in rHuEPO-treated patients. Our data suggest that endothelial injury, TF pathway components and peripheral serotonergic system disturbances may predispose to thromboembolic complications and play a role in the pathogenesis of atherosclerosis in uremic patients, particularly treated with rHuEPO. Increase in TFPI may compensate the increase in TF in these patients.

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation; Blood Platelets; Case-Control Studies; Endothelium, Vascular; Erythropoietin; Female; Humans; Lipoproteins; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Serotonin; Thromboplastin; Thrombosis; Uremia

Topics: Anemia; Cardiovascular Diseases; Catheters, Indwelling; Erythropoietin; Europe; Health Surveys; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Practice Guidelines as Topic; Survival Analysis; Thrombosis

Children with sickle-cell anaemia are predisposed to thrombotic strokes, the aetiology of which is unclear. We propose that erythropoietin, produced in response to chronic anaemia, is responsible for changes in platelet reactivity with a resulting increase in thromboses. This hypothesis is based on reports of enhanced aggregability of erythropoietin-driven platelets and an increased rate of thrombosis in patients receiving large doses of recombinant erythropoietin. Experiments in animals have shown that erythropoietin stimulates synthesis of platelets, that erythropoietin-driven platelets are hyper-reactive compared with age-matched control platelets, and that erythropoietin is pro-thrombotic. These data suggest that erythropoietin-dependent changes in platelet reactivity may potentiate thrombosis in sickle-cell anaemia, particularly in children who, compared with adults, have markedly higher erythropoietin concentrations and incidence of strokes.

Topics: Adult; Anemia, Sickle Cell; Animals; Case-Control Studies; Cerebrovascular Disorders; Child; Erythropoietin; Humans; Platelet Activation; Platelet Aggregation; Recombinant Proteins; Thrombosis

Topics: Anemia, Sickle Cell; Erythrocytes; Erythropoietin; Humans; Kidney Transplantation; Theophylline; Thrombosis

Topics: Anemia, Sickle Cell; Blood Platelets; Child, Preschool; Erythropoietin; Humans; Infant; Kidney Failure, Chronic; Recombinant Proteins; Thrombosis

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Erythropoietin; Female; Humans; Male; Middle Aged; Polytetrafluoroethylene; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Thrombosis

Erythropoietin (EPO) has been previously shown to affect platelet as well as red cell production. In addition, recent studies demonstrated that platelets from EPO-treated dogs are hyperreactive towards thrombin when compared to age-matched, control platelets. This report extends these observations by quantitating the thrombogenic potential of EPO in dogs. Dogs with arterio-venous (A-V) shunts received 100 U EPO/kg/day for 6 days, and thrombogenicity was serially monitored by insertion of a thrombotic surface into the A-V shunt. The resulting experimental thrombi were analyzed for platelet and erythrocyte content after formalin-fixation and chymotrypsin digestion, a technique which allows non-isotopic quantitation of cellular components. By day 5 of EPO-administration all animals demonstrated a significant increase in platelet and red cell content of the experimental thrombi; the average increase in platelet number was 2.94 +/- 0.12 fold (mean +/- 1 SE; n = 3; p = 0.006) above baseline while that for red cells was 2.46 +/- 0.18 fold above baseline (p = 0.023). After cessation of EPO, thrombogenicity returned to normal. During EPO-treatment, the percentage of thiazole orange-positive (TO+) platelets increased significantly to 17.2 +/- 1.6% (mean +/- 1 SE; n = 3) on day 5 compared to a pre-treatment level of 8.5 +/- 0.9% (p = 0.029). Although the percentage of TO+ erythrocytes also increased during the short course of EPO administration, the change was not significant. Despite the increases in TO+ cells, total platelet and erythrocyte counts did not change significantly within the time frame of these experiments. Fibrin/fibrinogen content of the experimental thrombi was unaltered with EPO-treatment. These data demonstrate that human EPO is pro-thrombotic in dogs and, in conjunction with earlier studies, suggest that hyperreactive platelets may be responsible for the potentiated thrombogenicity.

Topics: Animals; Arteriovenous Shunt, Surgical; Blood Platelets; Dogs; Erythrocyte Count; Erythropoietin; Fibrin; Fibrinogen; Humans; Platelet Count; Recombinant Proteins; Thrombosis; Time Factors

Recombinant human erythropoietin (rHu-EPO) in the treatment of renal anemia might predispose to an increased risk of thrombotic complications. In an attempt to comprehend the involvement of the physiologic inhibitors of coagulation in this process, we studied 2 groups of hemodialysis patients. Group I included 21 patients receiving a starting dose of 90 IU/kg/week s.c., and group II included 17 patients without rHu-EPO. The following coagulation tests were performed before rHu-EPO treatment, and after 1, 6 and 12 months: prothrombin time; activated partial fistula thromboplastin time; fibrinogen; plasminogen activity; antithrombin III activity; protein C activity; total and free protein S antigens, and C4b binding protein. Only the latter three parameters were changed in group 1, while high baseline levels of protein S antigens were found in both groups. A decrease in total and free protein S was observed within 1 month of treatment. At the 6th month total protein S returned to near pretreatment values, whereas a significant fall in free protein S (p = 0.007) was observed. All three parameters returned to near baseline values by 12 months. These results suggest that protein S activity can be altered at the beginning of EPO therapy, a change that under favoring circumstances might contribute to the thrombotic events reported during the early phase of rHu-EPO treatment.

Topics: Anemia; Antithrombin III; Blood Coagulation; Catheters, Indwelling; Complement C4b; Erythropoietin; Female; Fibrinogen; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Partial Thromboplastin Time; Plasminogen; Protein C; Protein S; Prothrombin Time; Recombinant Proteins; Renal Dialysis; Thrombosis; Treatment Outcome

Topics: Adult; Anemia; Blood Coagulation; Blood Coagulation Tests; Case-Control Studies; Drug Monitoring; Erythropoietin; Humans; Ketanserin; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Renal Dialysis; Thrombosis; Uremia

Recombinant human erythropoietin (epoetin) therapy had a significant impact on the practice of nephrology before its widespread use in the dialysis arena. Since then, a number of long-term studies have provided physicians with parameters for optimizing therapeutic response and patient outcomes with epoetin therapy. Fears of accelerated hypertension syndromes or increased fistula clotting are recognized as largely unfounded. There is a marked improvement in well-being, as measured by both subjective and objective parameters, as the level of anemia is reduced. Fortunately, epoetin was recognized early as essential therapy in patients on dialysis and thus was reimbursed by the Health Care Financing Administration (HCFA) and other payers, albeit through various methods of payment. Why is it, then, that hematocrit levels are still averaging approximately 30%? Perhaps the basic concern that all practitioners share is the potential for increased morbidity at "higher" hematocrit levels. Increased access clotting was not reported in the recently completed Epogen (Epoetin alfa; Amgen Inc, Thousand Oaks, CA) phase IV postmarketing study. Needle size, however, needs to be considered, because higher blood flow rates accompanied by higher hematocrit levels may lead to increased hemolysis. The venous needle size is especially important in patients who experience large weight gains. It is important to keep these issues in mind as one decides on an appropriate hematocrit level for a given patient. Hull and Eschbach reviewed postdialysis data from patients with naturally occurring high hematocrit levels and found no major changes in hematocrit level, thus alleviating the concern of significant postdialysis inspissation as a common cause for fistula clotting.

Topics: Adult; Anemia; Arteriovenous Shunt, Surgical; Blood Flow Velocity; Blood Pressure; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Needles; Renal Dialysis; Thrombosis

According to some data treatment with human recombinant erythropoietin (EPO) in dialyzed patients leads to a more frequent occurrence of thromboses. One of the possible causes could be reduced fibrinolysis. The objective of the present study was to assess the effect of EPO in dialyzed patients on two key enzymes of fibrinolysis, i.e. the tissue activator of plasminogen (t-PA) and the inhibitor of the plasminogen activator (PAI-1).. In eight patients dialyzed for prolonged periods examined under otherwise equal conditions before EPO treatment (haematocrit 22.9%--median value) and after 9.5 weeks of EPO treatment (Recormon, s.c.) when a haematocrit of 30% was achieved, activities (chromogenic substrates) and antigens (ELISA of t-PA and PAI) were assessed. All examinations were made before and after venous occlusion. Between examinations made before treatment and during EPO treatment no significant difference was found in the t-Pa activities assessed before venous occlusion (before EPO 0.9 IU/ml--during EPO 0.6, not significant Wilcoxon's paired test) nor after venous occlusion (3.2-3.8, n.s.). PAI activities before venous occlusion (10.9 U/ml-18.3, n.s.) and after venous occlusion (9.7-11.5, n.s.) did not differ significantly either, when comparing values before and in the course of EPO treatment. Similarly as in the case of activities in antigens t-PA and PAI no difference was found before and during EPO.. No effect of EPO on the investigated indicators of fibrinolysis was found. The results of the presented investigation are at variance with the idea that EPO reduces fibrinolysis in dialyzed patients and thus contributes to the development of thrombotic complications.

Topics: Adult; Anemia; Erythropoietin; Female; Fibrinolysis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Thrombosis

Erythropoietin therapy for uraemic anaemia is associated with a high rate of hypertensive and thrombotic complications. The mechanism is unknown, but a change in cellular calcium control may be relevant to changes in blood pressure and thrombosis. Platelets were utilized as a model of vascular smooth muscle cells. The effects of erythropoietin therapy on platelet cellular calcium, assessed by fura-2, were measured in 25 patients receiving renal replacement therapy during a 6-month treatment period. Three patients failed to reach a target haemoglobin and were excluded from the analysis. Blood pressure increased in 11 of the remaining 22 subjects, eight requiring an increase in antihypertensive medication. There were no differences in cellular calcium control between the group in whom blood pressure rose and patients with stable blood pressure. Overall there was a fall of 24% in resting cytosolic calcium (baseline 69.2 +/- 5.1 to 52.5 +/- 3.0 nmol/l, P < 0.05) after 3 months of erythropoietin therapy. There was no change in the thrombin-stimulated peak response in the presence of extracellular calcium during therapy, although thrombin-stimulated intracellular release also fell at 3 months (baseline 769 +/- 61 versus 3 months 559 +/- 49 nmol/l, P < 0.01). This study suggests that intracellular free calcium control within platelets improves in response to erythropoietin therapy. However these changes appear not to be related to the development of hypertension.

Topics: Adult; Aged; Anemia; Blood Platelets; Blood Pressure; Calcium; Cytosol; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Thrombosis; Uremia

To elucidate causes of thrombotic complications early in the course of RHE treatment, the authors studied platelet function (by aggregation of washed platelets), cAMP and cGMP as well as TxB2 levels in blood plasma, red cell function (by MDA content) in 16 patients suffering from chronic renal failure (CRF) on hemodialysis. 8 of them had been on RHE for 1.5 months. It appeared that plasma levels of TxB2 and cGMP increased, thrombin-induced platelet aggregation slightly decreased, MDA in red cells on treatment month 1.5 rose. The authors made the conclusion that early in the course of RHE treatment the conditions promoting active thrombogenesis may arise as a result of red cell induced platelet activation due to increased number of red cells with poor resistance to oxidant damage and hemolysis. Application of RHE in CRF patients should be combined with antioxidant therapy, especially in patients at high thrombogenesis risk.

Topics: Adult; Blood Platelets; Combined Modality Therapy; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric; Thrombosis; Time Factors

The objective was to evaluate the effect of the treatment of anemia with recombinant human erythropoietin (EPO) on thrombosis of the vascular access used for hemodialysis. The research design was a prospective cohort study comparing EPO-treated hemodialysis patients with a comparison group matched for type of vascular access, clinical center, and age. All patients commencing hemodialysis in the study centers between March 1988 and July 1991 were eligible if either a graft or fistula had been used as a first permanent vascular access. There were 64 matched fistula pairs and 38 matched graft pairs. There were more patients with a history of cardiovascular disease in the EPO group than in the comparison group for both fistulae and grafts, 34 versus 14% for the former and 37 versus 5% for the latter. There was no difference between EPO and comparison groups with respect to time to first thrombosis of fistula, 11.3 versus 10.6%, respectively, by thrombosis of grafts among those treated with EPO--33.6 versus 11.2% (P = 0.02). EPO treatment does not increase the probability of fistula thrombosis, but there is an association with an increased probability of graft thrombosis.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; Cardiovascular Diseases; Catheters, Indwelling; Cohort Studies; Comorbidity; Diabetes Mellitus; Erythropoietin; Female; Humans; Immunologic Factors; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Thrombosis

To assess whether r-HuEPO (recombinant human erythropoietin) has any effect on thrombopoiesis in patients with chronic renal failure.. This was a retrospective study of 78 patients with chronic renal failure undergoing either haemodialysis (n = 57) or intraperitoneal dialysis (n = 21). All patients had a full blood count (in EDTA) measured before starting r-HuEPO and at monthly intervals thereafter up to six months. Variables studied were haematocrit, platelet count, mean platelet volume (MPV) and platelet distribution width (PDW). Other groups of control patients were also studied--patients with chronic renal failure receiving dialysis but not r-HuEPO (n = 40) and a group of patients with normal renal function who were receiving aspirin (n = 30).. There was a significant increase in mean haematocrit (p < 0.01) and in mean platelet volume (p < 0.001) over the six month period, but no change in either total platelet count or platelet distribution width in the patients with chronic renal failure receiving r-HuEPO. In contrast, both the control groups showed no significant change in MPV.. The results suggest that r-HuEPO affects thrombopoiesis and may be part of a group of humoral factors contributing to megakaryocyte development and maturation. Larger platelets are more reactive and may contribute to the increased risk of thrombosis associated with r-HuEPO.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Platelets; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Count; Recombinant Proteins; Retrospective Studies; Thrombosis

Three patients on chronic maintenance haemodialysis have progressively increased their haematocrit to reach values between 40 and 45%, a situation associated with an increased risk of thrombosis of their arteriovenous fistulae. Two of them had been submitted to repeated phlebotomies, which remained unsuccessful despite the induction of a profound iron deficiency in one of them. Hence, a trial with oral theophylline was performed in the three patients, resulting in a sustained decrease of the haematocrit (from 43.6 to 33%) and endogenous erythropoietin (from 46 to 15 mU/ml) levels. In two patients, theophylline therapy was stopped transiently due to gastrointestinal side-effects, which resulted in a rapid return to previous haematocrit levels; rechallenge with a better tolerated preparation, however, was efficient again. We conclude that oral theophylline appears to be an efficient treatment to control too high haematocrit levels in dialysis patients.

Topics: Administration, Oral; Arteriovenous Shunt, Surgical; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polycythemia; Renal Dialysis; Theophylline; Thrombosis

The pathogenesis of hypertension induced by recombinant human erythropoietin (rHuEPO) remains a subject of intense interest. The observation that patients treated with antiplatelet drugs never developed hypertension following rHuEPO therapy prompted us to study retrospectively the incidence and risk factors associated with the development of hypertension in 91 patients on renal replacement therapy who had commenced rHuEPO therapy in the last three years. Logistic regression analysis was used to determine the risk factors associated with the development or aggravation of hypertension during the first six months on rHuEPO therapy. The predictors were: age, gender, number of months on dialysis, antecedent of hypertension, use of antiplatelet drugs, and those parameters related with dose, route and magnitude of the hematological response to rHuEPO. Of the 91 patients studied, 34 developed hypertension (37%). Of the 34 patients who were on antiplatelet treatment, 2 (5.8%) developed hypertension, whereas among 57 who did not receive antiplatelet drugs, 32 (56%) developed it. By multiple logistic regression analysis, the best predictive variables over the development of hypertension were: age (odds ratio: 0.959, P = 0.02), antecedent of hypertension (odds ratio: 6.52, P = 0.002), and use of antiplatelet therapy (odds ratio: 0.030, P < 0.0001). The rest of the studied variables failed to explain the development of hypertension. Antiplatelet therapy may prevent the development of hypertension in patients treated with rHuEPO. Since the antiplatelet drugs used in this study did not have a significant hemodynamic effect, we infer that changes in platelet aggregability induced by rHuEPO may be involved in the pathogenesis of hypertension induced by this hormone.

Topics: Adolescent; Adult; Aged; Catheters, Indwelling; Confounding Factors, Epidemiologic; Erythropoietin; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Platelet Aggregation Inhibitors; Recombinant Proteins; Regression Analysis; Renal Dialysis; Retrospective Studies; Risk Factors; Thrombosis; Uremia

Patients with polycythaemia and normal controls have been studied to establish and subsequently test non-conventional criteria for the diagnosis of primary polycythaemia (primary proliferative polycythaemia, polycythaemia vera) as compared with conventional Polycythaemia Vera Study Group (PVSG) assessment. One criterion was erythroid colony formation from peripheral blood in a serum-free system, assayed alone and with the addition of recombinant human erythropoietin (Epo), interleukin 3 (IL3), or alpha interferon (alpha-IFN) (Dudley et al. 1990). The remaining criteria were non-culture associated and comprised platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), serum erythropoietin and clinical evidence of ischaemic vascular disease. The combination of culture associated and non-culture associated variables, by use of a simple additive scoring system, gave no false positive and only 6% false negative results in distinguishing primary polycythaemia from other polycythaemias and normal controls in those (34 patients Group A) used in its derivation. Testing the scoring system in a newly presenting group (25 patients Group B) was highly satisfactory with no false positives and only a few false negative results (14%). Use of these non-conventional criteria should allow more confident diagnosis of primary polycythaemia, where conventional clinical and laboratory assessment is inconclusive.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Biomarkers; Blood Platelets; Cells, Cultured; Colony-Forming Units Assay; Diagnosis, Differential; Erythrocytes; Erythropoietin; Female; Humans; Interferon Type I; Interleukin-3; Ischemia; Male; Polycythemia; Polycythemia Vera; Recombinant Proteins; Reference Values; Thrombosis

Erythropoietin (EPO) is highly efficacious in the treatment of the anemia of chronic renal failure. Evidence for a reported serious side effect, increased dialysis graft thrombosis, is equivocal. Sixty-four hemodialysis patients utilizing polytetrafluoroethylene (PTFE) grafts were treated with EPO. The patients served as their own historical controls. There were 1.188 thrombectomies and 0.222 mechanical problems per 1,000 patient-days prior to the initiation of EPO treatment. With EPO, the values were 0.656 and 0.222, respectively. Patients were separated into low-, medium-, and high-dose EPO groups and analyzed within groups for the effect of EPO and between groups for a dose-dependent response. According to an analysis of variance procedure, there was no statistically significant differences between the groups, which suggests that EPO is not thrombogenic to dialysis grafts.

Topics: Anemia; Blood Vessel Prosthesis; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Count; Polytetrafluoroethylene; Recombinant Proteins; Renal Dialysis; Thrombosis

An attempt was made to discover the aetiology of acquired portal vein thrombosis in 12 polycythaemic patients who did not show any obvious local or regional cause. In addition to the diagnostic criteria of polycythaemia vera, erythropoietin was determined and cultures of erythroblast precursors were examined. The patients could be divided into 3 groups, in the first of which the definite diagnosis of polycythaemia vera was made on the basis of the PVSG (Polycythaemia Vera Study Group) criteria and bone marrow biopsy (5 patients). In the second group (5 patients), there was a diagnosis of possible polycythaemia vera based essentially on the finding of a spontaneous growth of medullary CFU-E. Finally, diagnostic criteria for polycythaemia vera were absent in two patients. On the basis of these findings, the physiopathology of the association of portal thrombosis and polycythaemia is discussed, in particular polycythaemia secondary to hepatic ischaemia.

Topics: Adult; Blood Volume; Bone Marrow; Erythropoietin; Female; Hematocrit; Humans; Iron Deficiencies; Male; Middle Aged; Polycythemia Vera; Portal Vein; Splenomegaly; Thrombosis

Thrombin-antithrombin III complex concentrations (TAT-III) were measured in 18 anaemic haemodialysis patients treated with erythropoietin (Epo) and in four haemodialysis patients treated with i.v. iron dextran. There was a significant early increase in thrombin-antithrombin III in erythropoietin-treated patients which appeared to be independent of the response to erythropoietin (Epo responders (n = 14), pretreatment TAT-III median (range) 3.10 (2.70-9.10) micrograms/l; maximum TAT-III 19.48 (11.18-60.00) micrograms/l, P less than 0.001, Wilcoxon; Epo non-responders (n = 4), pretreatment TAT-III 3.15 (2.90-4.50) micrograms/l, maximum TAT-III 16.00 (10.31-36.12) micrograms/l, P less than 0.001). This was not seen in iron-dextran-treated patients (Pretreatment TAT-III 2.05 (1.90-9.48) micrograms/l, maximum TAT-III 5.60 (2.10-14.50) micrograms/l). The change was not related to haemoglobin, erythropoietin dose, or method of administration, and was transient in nature, thrombin-antithrombin III returning to pretreatment values after approximately 6 months in all patients (Epo responders 6.0(4.0-9.0) months, TAT-III 2.47 (1.30-9.23) micrograms/l; Epo non-responders 7.0 months, TAT-III 5.04 (2.10-7.00) micrograms/l). Increased thrombin-antithrombin III complex may reflect an effect of erythropoietin on microcirculatory factors, which could be relevant to the occurrence of adverse events during treatment.

Topics: Adult; Aged; Antithrombin III; Erythropoietin; Hemoglobins; Humans; Middle Aged; Renal Dialysis; Thrombin; Thrombosis

Topics: Adult; Erythropoietin; Female; Humans; Protein S Deficiency; Recombinant Proteins; Thrombosis; Venae Cavae

Topics: Catheters, Indwelling; Erythropoietin; Humans; Renal Dialysis; Risk Factors; Thrombosis

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Thrombosis

Two patients (one male and one female) with end stage renal disease on chronic hemodialysis were treated with recombinant human erythropoietin (r-HuEPO). Both patients developed significant clotting in the vascular access and extracorporeal circuits. Coagulation studies indicated that both patients acquired high levels of tissue-type plasminogen activator inhibitor (PAI) with deficiency in tissue-type plasminogen activator (t-PA) and consequent impaired fibrinolysis. Their fibrinolytic activity was normalized with danazol therapy in doses as low as 2-4 mg/kg given orally once daily. We conclude that r-HuEPO-induced thrombosis is associated with impaired fibrinolysis due to acquired elevation of PAI which can be effectively prevented by small doses of danazol.

Topics: Adult; Danazol; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Plasminogen Inactivators; Recombinant Proteins; Thrombosis

An increased incidence of fistula thrombosis has been reported in haemodialysis patients treated with recombinant human erythropoietin (rHuEpo). The present study sought to investigate this problem by measuring fistula blood flow, blood viscosity, and a variety of tests of coagulation and haemostasis in a group of ten haemodialysis patients treated with rHuEpo. Fistula blood flow did not alter during the first 12 months of rHuEpo despite a significant increase in whole-blood viscosity. Bleeding time improved in all ten patients after 4 months of therapy, and this improvement was maintained at 12 months. There were no significant changes in one-stage prothrombin time, kaolin cephalin clotting time, whole-blood clotting time, prothrombin consumption index, plasma fibrinogen factor VII, factor VIII, antithrombin III, or platelet aggregability to ADP over the first 4 months of rHuEpo. In contrast, protein C decreased from 84.3 to 66.4% (P less than 0.01) and protein S from 124.1 to 68.3% (P less than 0.001) over the first 4 months. By 8 and 12 months, the concentrations of these substances had returned to pretreatment values. The levels of protein C and S attained at 4 months are known to predispose to thrombosis, and it is possible that this effect may contribute to the increased incidence of fistula thrombosis observed in haemodialysis patients treated with rHuEpo.

Topics: Adult; Arteriovenous Shunt, Surgical; Blood Coagulation; Blood Flow Velocity; Blood Viscosity; Erythropoietin; Female; Glycoproteins; Hemostasis; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Protein C; Protein S; Renal Dialysis; Thrombosis

Correcting anemia in hemodialysis patients may cause an increased incidence of vascular access clotting. Therefore, the incidence of clotting in patients before and during therapy with epoetin alfa was investigated. The records of 45 hemodialysis patients were accessed by computer for data concerning thrombectomy procedures and administration of epoetin alfa during two 13-week periods. Before therapy, 2 out of 45 patients had clotted accesses for a rate of .18 thrombectomy procedures per patient year. During therapy, 7 out of 45 patients had 11 clotted accesses for a rate of 1 thrombectomy procedure per patient year. Clotting incidence was shown to be increased during the epoetin alfa therapy period. The consequences of delaying a dialysis treatment due to a clotted access may be significant and even life-threatening. Both physicians and nurses must have a good understanding of the possible role of epoetin alfa in access thrombosis for patient management.

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Anastomosis; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Thrombosis

Topics: Adult; Anemia; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Renal Dialysis; Thrombosis

Topics: Adult; Aged; Anemia; Blood Viscosity; Erythrocyte Aggregation; Erythropoietin; Female; Fibrinogen; Hematocrit; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Rheology; Thrombosis

Topics: Adult; Erythropoietin; Female; Humans; Kidney Transplantation; Postoperative Complications; Thrombosis

Erythropoiesis was evaluated in 37 patients with sickle cell anaemia, 26 of them children under 12 years of age. Mean haemoglobin, haematocrit, reticulocyte, and erythropoietin levels were similar for 11 who were asymptomatic, 11 with infections, and 12 in vaso-occlusive crisis. Mean haemoglobin, haematocrit, and reticulocyte values were significantly lower and the mean erythropoietin level significantly higher for three patients in aplastic crisis. Reticulocyte counts reflected erythropoietic activity during the asymptomatic state but were variable during infection and crisis. No erythropoietic inhibitory activity was found in any of the four clinical states. It has been suggested that erythropoietin production decreases during infection. Patients in this study responded appropriately to stress, showing no decrease in erythropoietic activity during acute infection or crisis.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Blood Cell Count; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Infant; Infections; Male; Reticulocytes; Thrombosis; Vascular Diseases

Hypertension was found in four patients after unilateral renal-artery thrombosis following blunt abdominal trauma. In one patient, who was followed up from the time of injury, renin hypersecretion and secondary aldosteronism developed within a few days, and hypertension was present 12 weeks later. Increasing haemoglobin and raised blood-erythropoietin concentrations were also found. In the three other patients, hypertension was found casually within 3 years of trauma. In all patients, unilateral renin production by the affected kidney was significantly increased. Nephrectomy of the diseased kidney corrected hypertension and endocrine abnormalities in all patients. The delayed onset of hypertension despite early activation of the renin/angiotensin/aldosterone axis accords with the course of events observed in experimentally induced hypertension in rats, and suggests that several weeks or even months are required for hypertension to develop after sudden renal-artery occlusion in man. Slowly acting mechanisms, probably initiated by hypersecretion of renin, may be responsible for the hypertension.

Topics: Abdominal Injuries; Adult; Aldosterone; Angiotensin II; Blood Pressure; Erythropoietin; Female; Hemoglobins; Humans; Hypertension, Renal; Male; Middle Aged; Nephrectomy; Renal Artery; Renin; Sodium; Thrombosis

Atrial thrombosis is a common lesion in female Taconic Swiss mice fed a high-fat (28%), low-protein (8%), hypolipotropic diet for 10 wk or longer. After the third week of such feeding the mice studied here were injected with either erythropoietin, washed, packed red blood cells, lysed red blood cells, plasma or physiological saline.In mice receiving injections of lysed red cells, plasma or saline, respectively 75, 54 and 82% of those surviving for 10 wk had developed atrial thrombosis. Hematocrits were 9.3% or below in these groups. Hematocrits were maintained at an average of 33.0% in the erythropoietin group and 32.4% in the transfused (packed erythrocytes) group. Only one of the erythropoietin injected animals and none of the transfused animals developed atrial thrombosis. The evidence indicates that the anemia induced by the experimental diet results from lack of erythropoietin production or activity and that the hypoxia of anemia plays a role in the development of atrial thrombosis.

Topics: Anemia; Animals; Blood Transfusion; Body Weight; Diet; Dietary Fats; Erythrocytes; Erythropoietin; Female; Heart Atria; Heart Diseases; Hematocrit; Injections, Intraperitoneal; Mice; Plasma; Reticulocytes; Sodium Chloride; Thrombosis

Topics: Anemia; Animals; Blood; Epoetin Alfa; Erythropoietin; Haplorhini; Infarction; Ischemia; Kidney Transplantation; Macaca mulatta; Nephrectomy; Research; Thrombosis; Transplantation, Autologous; Uremia