Red Cell Mass Research Articles

INTENSITY OF PEROXIDATION PROCESSES IN THE LIVER OF RATS UNDER EXPERIMENTAL ULCEROGENESIS AGAINST THE USAGE OF THE MINERAL FRACTION OF PELOIDS OF BOLSHOYE YASHALTINSKOYE LAKE

In the pathogenesis of gastric ulcer, great importance is attached to the theory of oxidative stress. The change in the activity of the antioxidant system and the intensity of peroxidation is very significant in shifting the balance between aggression factors and the mechanisms of protecting the tissues of the gastroduodenal zone involved in the formation of ulcerative defects. When choosing means of correcting pathologies of the gastrointestinal tract, much attention is paid to the silt-sulfide peloids. Lake Bolshoye Yashaltinskoye in the territory of the Republic of Kalmykia has a large stock of silt-sulphide muds with a wide range of therapeutic properties. In this paper, the effect of the mineral fraction of peloids on the oxidative stress indices in the acetate model of ulcer formation in rats was studied, namely, the rate of spontaneous and ascorbate-dependent lipid peroxidation (LPO) in the liver homogenate was analyzed. The activity of the antioxidant system in the modeling of experimental ulcerogenesis was determined by the content of one of the protective enzymes – catalase – in the blood (serum and red cell mass (RCM)). The present study revealed that the use of the mineral fraction of the peloids of the Bolshoye Yashaltinskoe under conditions of experimental ulcerogenesis promoted an increase in the activity of the body’s antioxidant system. This was manifested in a statistically significant increase in the activity of erythrocyte catalase in animals of the experimental group in comparison with the control group.The materials of the article can be useful for substantiating the effectiveness of antioxidants for the therapy of gastric and duodenal ulcer.

The WHO diagnostic criteria for polycythemia vera—role of red cell mass versus hemoglobin/hematocrit level and morphology

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.

Accurate Assessment of Blood Loss During Cesarean Delivery Improves Estimate of Postoperative Hemoglobin [17B

INTRODUCTION: The need for red blood cell transfusion for patients having cesarean delivery is ideally based on an evaluation of both clinical indicators and laboratory studies. In practice, transfusions are often given to women based on estimated intraoperative blood loss (EBL) and/or the postoperative hemoglobin level. Since visual estimation is known to be inaccurate, we postulated that a more accurate determination using a novel colorimetric device would be better correlated with postoperative day one hemoglobin than visual estimation. METHODS: A formula incorporating both height and weight was used to estimate blood volume and, by including preoperative hemoglobin, red cell mass. Assuming a constant blood volume either the visual EBL (n=32) or EBL using a novel colorimetric device (Triton System™, Gauss Surgical) that incorporates a mobile application to photograph sponges and canisters and calculate their hemoglobin content (n=53) was used to predict the postoperative day one hemoglobin value in patients where either the visual estimate or colorimetric estimate was >1,000 ml (a common definition of hemorrhage). RESULTS: The predicted postoperative day one hemoglobin level using the device was better correlated with the actual value (R squared=0.319) than the predictions using visual EBL (R squared=0.035) (P=.027). CONCLUSION: In mothers with high blood loss, EBL using the novel device was a more accurate predictor of the postoperative day one hemoglobin than visually estimated blood loss. Clinical use of this information has the potential to improve transfusion practice in cesarean delivery patients and positively impact maternal health.

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double‐blinded, cross‐over study. Sixteen healthy subjects were tested with placebo, or low‐dose rhEPO for 2 weeks, or high‐dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high‐dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin‐angiotensin‐aldosterone system from changes in renal hemodynamics. This may serve as a negative feed‐back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin‐angiotensin‐aldosterone system.

Abstract P1-10-15: Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles

Abstract CD47 is a cell surface transmembrane protein that binds to signal regulatory protein alpha (SIRPα) on macrophages and results in a “don't eat me” signal that inhibits phagocytosis. Breast cancer cells, both primary and metastatic, frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. Anti-CD47 monoclonal antibodies (mAbs) block the CD47/SIRPα interaction and promote tumor cell destruction via phagocytosis. Anti-CD47 mAbs also contribute to an anti-tumor T-cell response in immune-competent mice. Therefore, anti-CD47 antibodies represent a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. CD47 is expressed on multiple cell types, including tumor cells and normal cells. Many anti-CD47 mAbs block the CD47/SIRPα interaction and cause phagocytosis of tumor cells, but do not directly induce the death of human tumor cells. Tioma has created new humanized anti-CD47 mAbs with novel and differentiated functional profiles to enhance functional heterogeneity. Ti-104, Ti-176 and Ti-108 block the binding of SIRPα to CD47 and increase phagocytosis of human tumor cells. They also induce cell death of human hematological and solid tumor cell lines (including breast cancer lines) in a cell autonomous manner. Cell death was determined by an increase in phosphatidylserine-positive/7AAD-positive tumor cells assessed by flow cytometry following incubation in media containing anti-CD47 mAb or a negative control immunoglobulin. In vitro, these mAbs bind to human tumor cell lines with apparent binding affinities ranging from low pM to low nM, depending on the cell line and method of analysis (solid-phase or cell-based ELISA, flow cytometry or surface plasmon resonance). In vitro, Ti-104 and Ti-108 bind to human RBCs, whereas Ti-176 has markedly reduced binding to human and cynomolgus monkey RBCs. In a four-week (once-weekly dosing) exploratory safety study in cynomolgus monkeys with Ti-176 and Ti-108, no dose-limiting toxicity or gross pathological or microscopic findings were identified after an initial dose of 5 mg/kg (Week 1) followed by doses of 50 mg/kg (Weeks 2, 3, and 4). Ti-176 treatment resulted in minimal decrease in red cell mass, hemoglobin and hematocrit, which corresponded in vitro to markedly reduced binding to cynomolgus monkey RBCs. Ti-108 caused transient reduction of RBC parameters comparable to some previously reported anti-CD47 mAbs. Ti-104, Ti-176 and Ti-108 showed potent, dose-dependent efficacy in multiple mouse tumor models, including in the MDA-MB-231 triple-negative breast cancer orthotopic model. These data provide the preclinical rationale for further evaluation of Ti-104, Ti-176 and Ti-108 as breast cancer treatments. Citation Format: Karr RW, Liu K, Hiebsch R, Capoccia B, Donio M, Crowley K, Puro R, Chanda S, Manning P. Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-15.

Polycythemia Vera.

Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of thromboembolic complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary.

Effect of Body Mass Index, Smoking, and Aspirin Administration on Polycythemia Incidences

Aims: Polycythemia is an increase in red cell mass as evidenced by increase in hemoglobin (Hb), hematocrit, and number of circulating erythrocytes. The aim of this study was to investigate the effect of some clinical manifestation on the occurrence of polycythemia including overweight, smoking, meat consumption, chronic diseases, previous history, family history, recurrent blood donation, and aspirin administration. Materials and Methods: This study was performed at The Iraqi National Blood Bank in Baghdad. Data including weight, height, and Hb levels were estimated personally from 80 patients attending on three different days at the bank for blood donation. Each of the patients were asked about having clinical manifestation tested in this study. Results: Hb levels were slightly elevated when body mass index values were increased. Approximately 61% of patients having high Hb levels were meat consumers compared to nonmeat consumers who did not have high Hb levels. About 36% of patients who had high Hb levels were smokers compared to 11% who were nonsmokers. A total of 17% of patients having high Hb levels were taking aspirin in comparison to 26% who were not taking this drug. Chronic diseases, family history, previous history, or recurrent donation seem to have unclear effect on Hb levels. Conclusion: Smoker and overweight people seemed to have higher Hb levels, whereas aspirin administration led to decreasing Hb levels. Other manifestation had little or no relationship with Hb levels.

Patient blood management strategies in total hip and knee arthroplasty

Background: Patient blood management in total hip and knee arthroplasty involves a three-pillar approach of optimizing red blood cell mass, minimizing blood loss, and managing anemia. We describe the effect of implementation of various strategies over a 7-year period. Methods: We prospectively collected blood transfusion data over a yearly quarter in the years of 2009, 2012, 2014, and 2015 with patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), primary and revision procedures. Evidence-based patient blood management strategies were introduced, including a tranexamic acid (TXA) protocol. The data were retrospectively analyzed, with observations of rates and appropriateness of blood transfusions in the context of changes in Australian National Blood Authority guidelines. Results: There was a significant reduction in transfusion rates from 2009 to 2015 in both THA (38.5%, 24.4%, 8.5%, and 12.5% for 2009, 2012, 2014, and 2015, χ2=17.9, P<0.05), and TKA (12.4%, 6.1%, 7.8%, and 2.1% for 2009, 2012, 2014, and 2015, χ2=4.2, P<0.05). This coincided with an increased adherence to national blood management guidelines in both THA and TKA (χ2=7.19, P=0.027). Conclusions: Patient blood management is multifaceted, and significant reductions in transfusion can be achieved in adherence to perioperative patient blood management guidelines. Tranexamic acid also is an important contributor in the improvement of transfusion rates in THA and TKA.

Effect of therapeutic phlebotomy on plasma volume in polycythemia patients

Background: Therapeutic phlebotomy (TP) helps in reducing the red cell mass thereby whole blood viscosity to improve tissue perfusion and oxygen delivery in polycythemia patients. We aimed to determine the plasma volume changes in polycythemia patients undergoing TP. Materials and Methods: We studied TP procedures in 134 patients undergoing 236 episodes prospectively. Patient clinical details were recorded to assess improvement in symptoms after the procedure. Plasma volume changes were calculated based on the difference between the pre- and postcollection blood volume. The influence of frequency of blood collected on plasma volume was analyzed. Results: A progressive reduction in hematocrit (1.7 ± 2.6 %) and hemoglobin (0.78 ± 0.5 g/dL) in relation to volume removed and frequency was observed . The mean blood removed during TP in these patients was 304 ± 58.1 mL. There was a progressive increase in plasma volume with respect to the frequency of TP (2.51 ± 1.58 mL/kg). Conclusion: Symptomatic improvements following TP were noted in 60% of patients. TP though commonly performed for reducing red cell mass in polycythemia had poor compliance from patients, resulting in failure to achieve desired levels.

Evaluation of efficacy of jaggery and raisins as supplements in iron deficiency anemia among medical undergraduate students in South India

Background: Anemia is defined as a reduction of the total circulating red cell mass and is a major public health problem in India. More than 1.6 billion anemic people have manifestations of iron deficiency anemia (IDA). The best and most sustainable strategy for preventing micronutrient (iron and folic acid) deficiency is dietary supplement. Adolescent age group is the window of opportunity to correct their nutritional status by providing additional food supplements and prevent future consequences of nutritional deficiencies. Aims and Objectives: This study aims to evaluate the effectiveness of jaggery and raisins as supplements in treating iron deficiency anemia. Materials and Methods: This is a prospective interventional clinical endpoint study conducted among 50 female medical undergraduate students. They randomly received oral nutritional supplement (jaggery balls - 5 g and raisins - 5 g) once daily in the morning for 8 weeks. Body weight and complete blood count were assessed before and at the end of 8 weeks of intervention. Results: After 8 weeks of daily supplementation of jaggery and raisins, we observed that there was a significant rise in the mean hemoglobin (Hb) level to 11.79 ± 1.07 (P < 0.0001) and also a significant rise in the mean red blood cell count to 4.22 ± 0.30 (P < 0.0001) compared to baseline values. Conclusion: The outcome of this study proved the effective role of the nutritional supplementation in improving the Hb status in IDA. Combination of jaggery with raisins proved to be a better natural food supplement to overcome IDA without prominent side effects as observed with oral and parenteral iron preparations. It can also be used as a prophylactic strategy to combat iron deficiency in vulnerable population.

Safety Evaluation of Lipid Nanoparticle-Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey.

The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested.24 hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ-inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms.

V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombosis is a leading cause of mortality and morbidity in MPNs, the mechanisms underlying their pathogenesis are unclear. Here, we identified pleckstrin-2 (Plek2) as a downstream target of the JAK2/STAT5 pathway in erythroid and myeloid cells, and showed that it is upregulated in a JAK2V617F-positive MPN mouse model and in patients with MPNs. Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality in JAK2V617F-knockin mice. Additionally, we demonstrated that a reduction in red blood cell mass was the main contributing factor in the reversion of vascular occlusions. Thus, our study identifies Plek2 as an effector of the JAK2/STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs, pointing to Plek2 as a viable target for the treatment of MPNs.

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans

The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection-including BRINP3, NOS2, and TBX5-are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.

Intravascular Volume Profiles in Patients With Class I and II Systolic Heart Failure: Heterogeneity and Volume Overload Are Common Even in Mild Heart Failure

BackgroundAlthough volume overload is a commonly described clinical feature of advanced heart failure (HF), less is known regarding volume profiles of patients with less severe class I and II HF. MethodsIntravascular volume was quantitated by radiolabeled-albumin indicator-dilution technique in clinic outpatients. ResultsForty-six patients (age 61 ± 13years, left ventricular ejection fraction 30 ± 8%) were prospectively evaluated with 28 undergoing repeat evaluations at 1 year. There was no difference in averaged total blood volume (TBV) at baseline between class I (N = 26) and II (N = 20) patients (5.6 ± 1.6vs 6.0 ± 1.3 L, P = .368) and at 1-year of follow-up. However, there was marked heterogeneity in plasma volume (–13% to +69% of normal) and red cell mass (RBCM –31% to +50%) profiles with TBV expansion identified in 46% of the cohort, whereas only 48% had a normal TBV. RBCM deficit (true anemia) was common (39%), but a low hemoglobin concentration was accurate in identifying anemia in only 11% of the cohort. RBCM excess (polycythemia) also was identified in 20% of the cohort. ConclusionsMarked heterogeneity in plasma volume and RBCM volume profiles is present even in mild HF, and identifying volume overload, which was common in early HF, has the potential to help guide therapy in the reduction of HF progression. Intravascular volume as a modifiable risk factor in early HF warrants further study.

Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia.

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.

Thermal injury of the skin induces G-CSF-dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice

Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent. Given that elevated G-CSF levels also have been associated with lower hemoglobin levels and increased transfusion requirements in trauma victims, we postulated that G-CSF mediates postburn EPO resistance. In ACI mice, we found that bone marrow erythroid differentiation, viability, and proliferation are impaired after thermal injury of the skin. These changes in the marrow were associated with attenuated phosphorylation of known EPO-responsive signaling nodes, signal transducer and activator of transcription 5 (STAT5) Y694 and STAT3 S727, in bone marrow erythroid cells and developed despite highly elevated levels of endogenous EPO. Severely blunted STAT5 Y694 phosphorylation in bone marrow erythroid cells after exogenous EPO supplementation confirmed that EPO signaling was impaired in ACI mice. Importantly, parenteral administration of anti-G-CSF largely rescued postburn bone marrow erythroid differentiation arrest and EPO signaling in erythroid cells. Together, these data provide strong evidence for a role for G-CSF in the development of ACI after burn injury through suppression of EPO signaling in bone marrow erythroid cells.

Postpartum obstetric red cell transfusion practice: A retrospective study in a tertiary obstetric centre.

Traditional management of anaemia due to postpartum haemorrhage (PPH) has relied upon salvage therapy with red cell transfusion. Recently published guidance recommends a change in approach toward holistic patient blood management. To determine whether postpartum red cell transfusion practices are consistent with best practice and to identify opportunities for improvement. A retrospective audit of postpartum red cell transfusions was conducted at a tertiary level obstetrics unit. Relevant clinical and laboratory data were collected for all cases of postpartum red cell transfusions and PPH. Clinical decision making and appropriateness of transfusions were evaluated. Among the 3235 women who delivered in 2013, 110 (3.4%) received a postpartum red cell transfusion. About 101 of the transfusions were associated with primary PPH. Overall PPH complicated 460 (14.2%) deliveries. Antenatal anaemia was identified as a major correctable risk factor for transfusion in women who experienced PPH (odds ratio 6.55, 95% CI: 3.17-13.6). Volume of blood loss and the aetiology of PPH were additional risk factors for transfusion. Transfusion was associated with lower birth weight and increased maternal length of stay. Transfusion triggers were more likely to be appropriate when transfusion took place in the operating theatre, within 12h of delivery and when prescribed by anaesthetists. Post-transfusion Hb levels were uniformly above target for all women transfused. A significant number of red cell transfusions were outside the recommendations of the new guidelines. Maximising red cell mass during pregnancy and improving transfusion practices were identified as opportunities for future improvement.

74 Multisystem manifestations of cyanotic adult congenital heart disease: review of prevalence and current practice on the norpap database

IntroductionAdults with congenital heart disease may be cyanotic either from unrepaired cyanotic conditions, or due to the failure of palliative procedures to completely separate the systemic and pulmonary circulations. Clinicians...

Peripartum Care of the Jehovah's Witness Patient.

Postpartum hemorrhage is a leading cause of maternal mortality. Jehovah's Witnesses (JWs) refuse allogeneic blood transfusion, and thus treatment of hemorrhagic complications in this patient population is complex. Recognition and respect for religious beliefs are essential when caring for the JW parturient and several ethical and legal considerations must be taken into account. Interdisciplinary teamwork and communication as well as active patient participation are critical in the decision-making process for JW patients. Various techniques and technologies are available to optimize red blood cell mass, minimize bleeding, increase tolerance to anemia and support multiorgan derangements derived from antepartum and postpartum hemorrhage.

A Novel Approach to Predict 24-Hour Energy Expenditure Based on Hematologic Volumes: Development and Validation of Models Comparable to Mifflin-St Jeor and Body Composition Models

BackgroundAccurate prediction of 24-hour energy expenditure (24EE) relies on knowing body composition, in particular fat-free mass (FFM), the largest determinant of 24EE. FFM is closely correlated with hematologic volumes: blood volume (BV), red cell mass (RCM), and plasma volume (PV). However, it is unknown whether predicted hematologic volumes, based on easily collected variables, can improve 24EE prediction. ObjectiveThe aim was to develop and validate equations to predict 24EE based on predicted BV, RCM, and PV and to compare the accuracy and agreement with models developed from FFM and with the Mifflin-St Jeor equation, which is recommended for clinical use by the Academy of Nutrition and Dietetics. DesignParticipants had body composition measured by underwater weighing and 24EE by respiratory chamber. BV, RCM, and PV were calculated from five published equations. Participants/settingNative American and white men and women were studied (n=351). Participants were healthy adults aged 18 to 49 years from the Phoenix, AZ, metropolitan area. Main outcome measureAccuracy to within ±10% of measured 24EE and agreement by Bland-Altman analysis. Statistical analysisRegression models to predict 24EE from hematologic and body composition variables were developed in half the dataset and validated in the other half. ResultsHematologic volumes were all strongly correlated with FFM in both men and women (r≥0.94). Whereas the accuracy of FFM alone was 69%, four hematologic volumes were individually more accurate (75% to 78%) in predicting 24EE. Equations based on hematologic volumes plus demographics had mean prediction errors comparable to those based on body composition plus demographics; although the Mifflin-St Jeor had modestly better mean prediction error, body composition, hematologic, and Mifflin-St Jeor models all had similar accuracy (approximately 80%). ConclusionsPrediction equations based on hematologic volumes were developed, validated, and found to be comparable to Mifflin-St Jeor and body composition models in this population of healthy adults.