bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shortened Lifespan of Red Blood Cells and the Effects of Erythropoietin in Rats with Nephrogenic Anemia.
Authors: Iwatsuki Yoshiyuki , Kitamura Koki , Suzuki Ken-ichi 
Published: October 2019

Abstract
Abstract 1977
Poster Board I-1000
Anemia is a common complication of chronic kidney disease (CKD), mainly due to the inability of the kidneys to secrete enough erythropoietin to adequately stimulate hematopoiesis. Further, given that the lifespan of red blood cells (RBCs) has been reported to be reduced in CKD patients, this reduction in RBC lifespan is believed to be a part of the etiology of renal anemia. In the present study, we focused on RBC survival and measured the lifespan of RBCs in rats with nephrogenic anemia. We also examined the effects of erythropoietin on RBC lifespan in this anemia model. Nephrogenic anemia was induced by oral administration of adenine (600 mg/kg/day for 10 days) to male Wistar rats. Progressive, serious anemia associated with increased levels of plasma creatinine was observed in the rats. On Day 40, the number of RBCs and hemoglobin (HGB) levels were lower in the adenine-treated rats than in normal, control rats (normal: 930×104/μL, anemic: 677×104/μL for RBC and normal: 17.2 g/dL, anemic: 13.4 g/dL for HGB). However, the number of reticulocytes did not change in the anemic rats (normal: 299×103/μL, anemic: 329×103/μL, P = 0.102). The percentage of annexin V-binding erythrocytes was increased in anemic rats (normal: 0.77%, anemic 1.76%) and inversely correlated with RBC count and HGB levels, suggesting that apoptosis of RBCs increased as anemia progressed. Taking these findings into account, we measured the lifespan of RBCs in rats with nephrogenic anemia. We transfused 5-chloromethylfluorescein diacetate (CMFDA)-labeled RBCs from normal donor rats into either normal or anemic recipients and determined the number of labeled RBCs present in the peripheral blood at various time points thereafter. The time course of the reduction in the percentage of labeled RBCs in peripheral blood revealed that the half-life (t1/2) of RBCs in anemic rats was shorter than in normal rats (normal: 22.5 d, anemic: 13.3 d). This reduction in RBC lifespan was also observed in a rat model of cisplatin-induced renal anemia. Injection of anemic rats with recombinant human erythropoietin (rhEPO) restored the number of RBCs and HGB concentration to normal levels. However, the t1/2of RBCs in these rats was not changed. The clearance of RBCs in anemic rats does not appear to be influenced by rhEPO injection. In conclusion, the survival of RBCs was reduced in rats with nephrogenic anemia, an observation consistent with the shortened survival time of RBCs in renal failure patients. This finding suggests that this model is suitable for investigating drugs which may be used in the treatment of renal anemia. Further, because EPO therapy did not affect the lifespan of RBCs, agents which improve the shortened RBC survival inherent in CKD patients may be useful in treating renal anemia.

Disclosures:
Iwatsuki: Astellas Pharma Inc.: Employment. Kitamura:Astellas Research Institute of America LLC: Employment. Suzuki:Astellas Pharma Inc.: Employment.
TRIB3 Pseudokinase Is Induced Via An EPO/EPOR/STAT5 Pathway, Markedly up-Modulated in Late-Stage Erythroblasts, and Plays An Essential Non-Redundant Role During Stress Erythropoiesis.
Authors: Dev Arvind , Wojchowski Don M. 
Published: October 2019

Abstract 1985
Poster Board I-1007
TRIB pseudokinases have been implicated as pro-leukemogenic factors, and candidate regulators of insulin-dependent glucose utilization, adipogenesis and obesity. In a hematopoietic context, we have discovered that TRIB3 is a major new EPOR/JAK2/STAT5 response factor which furthermore is selectively elevated (among TRIB-1, -2 and -3) ≥ 10 fold in late-stage murine and human erythroblasts. We therefore have hypothesized that TRIB3 may selectively affect stress erythropoiesis, and have critically addressed this problem by generating novel TRIB3flox/flox and TRIB3-null mice. At steady state, hematopoiesis among TRIB3-null mice is largely unperturbed. When challenged with hemolytic anemia, however, TRIB3- deficient mice exhibit worsened anemia (increased severity, and recovery time). Analyses of possible stage-specific effects further indicate faltered erythropoiesis at relatively late Kitneg CD71high Ter119pos erythroblast stage. Recently, TRIBs have been revealed to act as apparent E3 ubiquitin ligase coupling factors. It is therefore intriguing to speculate that TRIB3 may act selectively during stress erythropoiesis to target and decay a key late-stage negative regulator.

Disclosures:
No relevant conflicts of interest to declare.
Chronic Deferasirox Administration Decreases Hepatic Oxidative Stress and Apoptosis in the Iron Overloaded Gerbil.
Authors: AL-Rousan Rabaa , Katta Anjaiah , Paturi Satyanarayana , Kidd Brent , Manzoor Kamran , Walker Ernest , Blough Eric 
Published: October 2019

Abstract
Abstract 1996
Poster Board I-1018

Background:
Iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis) and is associated with an increased risk of developing liver fibrosis, cirrhosis, and hepatocellular carcinoma. Deferasirox is a novel oral chelator with high iron-binding potency and selectivity. Here we investigate the ability of deferasirox to remove excessive hepatic iron and prevent or reverse iron induced hepatic injury.

Methods:
Adult male Mongolian Gerbils were randomly divided into three groups: control, iron overload, and iron overload + deferasirox treatment (n = 8 / group). Iron overload animals received iron dextran 100mg/kg i.p /5d for 10 wks while deferasirox was given 100mg/kg/d p.o for 1-,3-, or 9- months. Hepatic iron levels were determined by inductively coupled plasma atomic emission spectrometry and Prussian blue staining was performed to examine iron deposition in the corresponding tissues. Immunoblot and immunohistochemical analyses for markers of oxidative stress were employed to assess effects of deferasirox treatment on hepatic protein oxidation and superoxide levels. TUNEL assay was employed to examine the extent of hepatic apoptosis.

Results:
Compared to the non-treated iron overload group, deferasirox treatment reduced hepatic iron levels by 21.3%, 43.5%, and 47.4% after 1, 3, and 9 months of treatment, respectively (p<0.05). Prussian blue staining and histological analysis detected frequent iron deposition, evidence of hepatic damage, and lipid accumulation in hepatic tissue of the iron overloaded group. Iron deposition was significantly diminished with deferasirox treatment and no evidence of lipid accumulation was observed. Immunoblotting demonstrated that iron overload caused 2- fold increase in hepatic ferritin expression (p< 0.05) which was reduced by 47.5% following three months of deferasirox treatment (p< 0.05). In addition, deferasirox significantly reduced hepatic protein oxidation and superoxide abundance. The percentage of TUNEL-positive nuclei in the deferasirox treated livers was 41.0% lower than that of iron overloaded group (p<0.05).

Conclusions:
These findings suggest that chronic deferasirox treatment may decrease iron-induced hepatic oxidative stress and apoptosis. Decrease in ROS accumulation in the liver may be the possible mechanism of this protective effect. Further studies are underway to delineate specific mechanisms.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation of Alternative, “Low-intensity” Induction Regimens in Elderly Adults with Acute Myeloid Leukemia (AML).
Authors: Feldman Eric J. , Ritchie Ellen , Gergis Usama , Mayer Sebastian , Scandura Joseph M. , Christos Paul J. , Wissa Usama , Roboz Gail J. 
Published: October 2019

Abstract
Abstract 2066
Poster Board II-43
From 1999 to 2009, 298 adults, age 60 yrs and above, received initial induction therapy for untreated AML at Weill-Cornell Medical College/New York Presbyterian Hospital. Based on physician/patient preference and/or protocol eligibility, patients received either a traditional cytosine arabinoside/anthracycline-based induction regimen (n= 103) or an alternative, low-intensity regimen(n=195); either low-dose ara-C +/- arsenic trioxide (n=88) or tipifarnib +/- oral etoposide (n=107). Overall the median age was 72 yrs (range 60-89), 47% had an antecedent hematological disorder (AHD) and 42% had an unfavorable karyotype. Patients treated with low-intensity regimens were significantly older compared to those given standard induction (median age 75 vs 67 yrs) and had a higher percentage of unfavorable karyotypes (46% vs 33%). Complete remissions (CR) were achieved in 23% of patients receiving low-intensity regimens and 53% of patients treated with standard therapy. Thirty and 60 day mortality rates were 9.7% and 20.5% versus 14.5% and 25% for low-intensity and standard regimens respectively (p=0.29). Seventy two of the initial 195 patients (37%) treated with a low-intensity regimen received a second induction regimen for primary resistance or relapse; either a standard ara-C-anthracycline regimen (n=38) or a second non-intensive regimen (decitabine +/- gemtuzumab ozogamicin, low-dose ara-c, SGN-33,) (n=34). Overall 25/72 (35%) achieved a CR with salvage therapy; 16/38 CR's (42%) with standard induction and 9/34 CR's (26%) with a second low-intensity regimen. Median overall survival for all 298 patients was 6.7 months. By univariate analysis, no significant difference in survival was seen for patients initially treated with a low-intensity regimen compared to those receiving standard induction (median 6.2 vs 7.7 months; p=0.82 by log-rank test). By multivariate analysis, age over 75, prior AHD, unfavorable karyotype, ECOG performance status > 2, and male gender all predicted for shorter survival, whereas intensity of initial treatment did not. These results suggest that older patients with AML may receive initial therapy with a non-traditional, low-intensity induction regimen and have similar survival outcomes compared to patients given standard induction. A comparison of the quality of life of patients, as manifested by the percentage of days spent in hospital, frequency of transfusion support, and number of outpatient visits, will be presented. Death due to resistant disease remains the major problem for older patients with AML

Disclosures:
Off Label Use: arsenic trioxide to be used to enhance the effects of low-dose ara-C as part of a clinical trial.
Prevalence of Anti-Heparin Platelet Factor 4 Antibodies in Patients with Disseminated Intravascular Coagulation.
Authors: Fareed Jawed , Zhu He , Cunanan Josephine , Jeske Walter , Hoppensteadt Debra , Arif Hussain , Harry Messmore , Walenga Jeanine M. 
Published: October 2019

Abstract
Abstract 2094
Poster Board II-71
Disseminated intravascular coagulation (DIC) represents a complex syndrome with multiple pathophysiologic components. Most patients with DIC exhibit thrombocytopenic responses due to endogenous consumption of platelets. A systematic study on the prevalence on anti-heparin platelet factor 4 (AHPF4) antibodies and HIT syndrome in DIC patients has not been presented. To determine the prevalence of AHPF4 antibodies in patients with suspected DIC syndrome a total of 25 plasma samples were retrospectively analyzed utilizing the two commercially available methods (GTI, Brookfield, WI and Hyphen Biomedical, Paris, France). Out of 25 patients, 24 samples were positive for the AHPF4 antibody in the GTI method (OD>0.400), whereas only 16 were positive in the Hyphen Biomedical assay (OD>0.500). Interestingly, only 9 samples were positive in both of these assays. None of the positive samples in either the GTI or the Hyphen assay exhibited a positive 14C serotonin response. Additional analysis of these samples revealed that only 8 of these patients were previously exposed to heparin. Only 4 of the baseline samples were found to contain low levels of heparin as measured by anti-Xa method (< 0.2 U/ml). Additional analysis of these samples revealed the presence of platelet activation products such as platelet factor 4 (PF4), selectin and p-selectin. These studies suggest that circulating AHPF4 antibodies are non-functional and do not produce any thrombocytopenic responses. The elevated circulating PF4 levels and other cytokines may be contributory to the generation of these antibodies in the DIC patients.

Disclosures:
No relevant conflicts of interest to declare.
Persistant Inhibition of Thrombin Generation After Intravenous Administration of Enoxaparin in Primates.
Authors: Litinas Evangelos , Gray Angel , Sadeghi Nasir , Cunanan Josephine , Hoppensteadt Debra , Fareed Jawed 
Published: October 2019

Abstract
Abstract 2095
Poster Board II-72
The biologic half life (T12) of low molecular weight heparin (LMWH) is usually measured in terms of the circulating anti-Xa levels. Enoxaparin represents an unique LMWH whose biologic T12 is relatively longer than most LMWHs. Moreover, it is known that the antithrombotic effects of this agent last longer in comparison to the measurable circulating anti-Xa levels. Therefore besides the anti-Xa activity, additional non-measurable biologic effects are contributory to the clinical effects of this agent. Plasma based thrombin generation assays have recently become available to assess the effects of LMWHs such as enoxaparin. In these assays blood plasma samples are activated using different activators and the generated thrombin inhibition is measured. To measure the time course of thrombin generation inhibitory activity after an IV bolus dose of 0.5 mg/kg of enoxaparin into groups of primates (n=6-8), a commercially available thrombin generation method was employed (Technoclone, Vienna, Austria/DiaPharma, West Chester,OH). Blood samples were drawn from each of the primates injected at varying time points for up to 28 hours. A thromboplastin/phospholipids based reagent was used to generate thrombin and the results were recorded in terms of nm of thrombin formed. The baseline values ranged from 500-900 nm (710±60 nm), although a complete inhibition of thrombin generation was noted at 1 hour (24±8 nm), a slow and gradual reduction in the thrombin generation inhibition was noted with a T12 of 9 hours. Even at 28 hours after the administration of enoxaparin, sustained inhibition of thrombin generation was noted (30-50%). Interestingly, the circulating anti-Xa and anti-IIa activity gradually diminished to an almost non-detectable level at 6 hours. These studies suggest that enoxaparin produces antithrombotic actions by multiple mechanisms. Furthermore thrombin generation methods in plasma samples may provide a more sensitive assay for the monitoring of the effect of LMWH.

Disclosures:
No relevant conflicts of interest to declare.
Anticoagulation does Not Prevent Venous Thromboembolism Following IVC Filter Placement: A Retrospective Study of 702 Patients.
Authors: Narayan Anand , Streiff Michael B. , Hong Kelvin , Lee Adrea , Kim Hyun 
Published: October 2019

Abstract
Abstract 2104
Poster Board II-81

Purpose:
Inferior vena cava filters (IVCF) are extensively used in the United States to treat venous thromboembolism (VTE). Although IVCF prevent pulmonary embolism (PE), IVCF are associated with an increased incidence of deep vein thrombosis (DVT) and IVC thrombosis (IVCT). It remains unclear whether anticoagulation (AC) could reduce thrombotic events post-filter placement. The purpose of this study was to examine the impact of AC on clinical outcomes post-IVCF placement

Materials and Methods:
After institutional review board approval was obtained, consecutive patients who received an IVCF at the Johns Hopkins Hospital were identified using Current Procedural Terminology (CPT) codes. Demographic and clinical data were retrieved from the institutional electronic medical record (EMR). Clinical events including objectively-documented VTE were confirmed by an independent EPR review by two investigators. Clinical outcomes with and without AC were compared using non-parametric and parametric statistics. Marginal structural models were used to model the impact of anticoagulation on VTE

Results:
Between January 1, 2002 and December 31, 2006, 702 patients had an IVCF placed at the Johns Hopkins Hospital. AC was used in 276 patients(39.4%) post-filter placement. 46.8% of patients were female and 60.1% were white and these parameters did not differ based upon AC status (p > 0.45). Patients on AC were younger than patients not on AC (54.9 years versus 59.0 years, p = 0.0025). The most common reason for IVCF placement in both groups was a contraindication to AC. Patients subsequently treated with AC were equally likely to present with DVT (p = 0.852) but were more likely to present with PE (p < 0.001) and IVC thrombus (p = 0.043). Retrievable filter use was more common in patients who were treated with AC. (p = 0.002). The mean duration of follow up was 434 days (range 1 - 2638 days). Follow up was longer for patients on AC than patients not on AC (576 versus 341 days, p < 0.001). All-cause mortality was lower for patients treated with AC (37.7% versus 56.0%, p <0.001). Post-filter placement, VTE occurred in more patients on AC than off AC (63/235, 26.8% versus 54/378, 14.1%, p<0.001). DVT (20.3% versus 11.1%, p = 0.001), PE (7.3% versus 3.5%, p=0.027) and IVCT (6.9% versus 2.1%, p=0.002) were more common in patients who were treated with AC.

Conclusions:
In a large retrospective single center cohort study, AC use was associated with a reduced all cause mortality but an increased frequency of VTE in patients after IVCF placement. These data suggest AC may not protect patients from thrombotic complications associated with IVCF placement and warrant prospective confirmation. IVCF should be reserved for patients who have acute VTE and a contraindication to anticoagulation.

Disclosures:
No relevant conflicts of interest to declare.
Feedback Activation of Factor XI by Thrombin Is Essential for Hemostasis In Vivo.
Authors: Spronk Henri M. H. , Wilhelm Sabine , Van Oerle Rene , Knetsch Menno L. , Gailani David , Pawlinski Rafal , Mackman Nigel , Cate Hugo ten , Renné Thomas 
Published: October 2019

Abstract
Abstract 2127
Poster Board II-102
Background: The revised model of coagulation proposes that factor XI (FXI) can be activated by thrombin, which is generated upon activation of the tissue factor (TF) pathway. This concept, however, has not been tested in vivo. A recent study questioned the existence of this feedback loop and suggested that factor XII (FXII) is the sole activator of FXI. Here, we analyze the feedback activation of FXI in plasma and in genetically altered mice. Methods and results: Fluorescence-based assays indicated that particle-bound thrombin caused thrombin generation in plasma both in the absence of TF and in the presence of active site inhibited factor VIIa. Thrombin failed to activate FXII and thrombin generation was almost completely abolished by an anti-FXIa antibody and in FXI-deficient plasma. Surface bound thrombin induced complex formation of FXI, with its major inhibitor C1 inhibitor, even in FXII-deficient plasma in a time and dose dependent manner. To determine if thrombin-driven FXI activation is important for hemostasis in vivo we used TF deficient mice (low TF), which have severely reduced thrombin formation. Low TF mice were crossed with mice deficient in one of the intrinsic pathway proteases FXII, FXI, or FIX. Double deficiency in TF and either FIX or FXI resulted in the intrauterine death of embryos due to hemorrhage. In contrast low TF/FXII-null mice were viable and the bleeding phenotype was unchanged from low TF animals. Conclusions: Surface-bound thrombin, a model for fibrin clot-protected thrombin, generates thrombin in a FXI dependent manner, independently from FXII. In addition to corroborating an amplifying role of FXI in thrombin generation, we provide the first evidence that at low TF levels FXI is essential in generating a sufficient ambient level of thrombin to permit embryonic development.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Impact and Resource Utilization After Stem Cell Mobilization Failure in Patients with Multiple Myeloma and Lymphoma.
Authors: Gertz Morie A , Wolf Robert , Micallef Ivana N. , Gastineau Dennis A. 
Published: October 2019

Abstract
Abstract 2142
Poster Board II-119

High-dose chemotherapy in conjunction with autologous SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 through 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1,775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was “ optimal” (≥5×106) in 53%, “low” (≥2 to 5×106) in 25%,“ poor” (<2×106) in 10%, and “failed” (<10 CD34+ cells/mL) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. Other costs often omitted include the need for hospitalization, which was seen in 5% to 11% of the patients in our study. Parenteral antibiotics were needed when fever developed in 7% of patients with Hodgkin disease, 4% with non-Hodgkin lymphoma, and 24% with multiple myeloma who underwent mobilization using a chemotherapy pulse. When stem cell mobilization was not immediately optimal, subsequent attempts to mobilize failed completely in 3 of 42 patients (7%) with Hodgkin disease (3% of the original Hodgkin disease cohort), 56 of 157 (36%) with multiple myeloma (6% of the original myeloma cohort), and 50 of 328 (15%) with non-Hodgkin lymphoma (7% of the original non-Hodgkin lymphoma cohort). These usually unappreciated costs of stem cell mobilization failure highlight the need for more effective mobilization strategies.

Disclosures:
Gertz: genzyme: Research Funding.