bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seasonal Variation In the Occurrence of Venous Thromboembolism In Canada
Authors: Kondal Dimple , Tagalakis Vicky , Ciampi Antonio , Kahn Susan 
Published: October 2019

Abstract
Abstract 5120

Background.
The evidence in support of a seasonal variation in the occurrence of venous thromboembolism (VTE) is conflicting and based on studies of mostly small or moderate size, often single centered and moreover, have never included data from Canada which has clearly-defined seasons with wide temperature differences between winter and summer months.

Objectives.
We used discharge data from a population-level hospital registry to assess the occurrence of a seasonal pattern in hospital admissions with VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE)), DVT alone and PE alone in the province of Quebec, Canada.

Methods.
Using data from the province of Quebec's hospital discharge database (Med-Echo) which systematically records information on all hospital admissions in Quebec since 1967, we constructed a retrospective cohort of all individuals who had a first-time discharge diagnosis of DVT or PE between January 1, 1996 and December 31, 2004 and no prior discharge diagnosis for DVT or PE back to 1983. DVT and PE were defined based on the International Classification of Diseases, 9th edition, Clinical Modification. VTE cases were grouped according to season and month of occurrence, and statistical significance of seasonal variation was determined using the Edwards' and Walter & Elwood test.

Results.
The cohort comprised of 45,588 (26,076 (57%) women and 19,512 (43%) men) admitted patients with incident VTE. The mean age was 62.5 years (SD 17.6) and 26,537 (58%) patients had DVT alone, 12,758 (28%) had PE alone and 6,239 (14%) had DVT with PE. Data by season showed a statistically significant difference with the lowest proportion of hospital VTE admissions in summer months (24.1%) and highest in winter (25.9%) months (p<0.0001). Seasonal variation in number of admissions by month was statistically significant for PE alone (p=0.0084; adjusted for total number of monthly hospital admissions for the Quebec province) with peak occurrence in November-December. There was no seasonal variation in monthly VTE (p=0.12) and DVT alone (p=0.87) admissions.

Conclusion.
Our large-scale population study provides evidence that in Quebec, Canada there is a seasonal variation in PE hospital admissions with an annual autumn peak. The underlying pathophysiologyic mechanisms are unknown and deserve further study.

Disclosures:
Tagalakis: Pfizer: Research Funding; Sanofi Aventis: Honoraria. Kahn:Sigvaris: Research Funding; sanofi-aventis: Advisory Board, Research Funding; Boehringer Ingelheim:.
Inherited Thrombophilia In Omani Women with Recurrent Pregnancy Loss
Authors: Farsi Khalil Al , Zadjali Shoaib Al , Falahi Karima Al , Al-Khabori Murtadha K. , Pathare Anil , Alkindi Salam 
Published: October 2019

Abstract
Abstract 5124

Background:
Recurrent pregnancy loss (RPL) is a common clinical problem. Inherited thrombophilia has been reported to be associated with RPL by different groups.

Methods:
We retrospectively analyzed the records of women who had thrombophilia testing for RPL, defined as 2 or more pregnancy losses, between the period of June 2006 and June 2010. The following thrombophilic disorders were included: protein C deficiency (PC), protein S deficiency (PS), anti-thrombin deficiency (AT), activated protein C resistance (APCR) and more recently, as molecular testing became available at our institution, factor V G1691A (FVL), prothrombin G20210A (PTG) and Methyl tetrahydrofolate reductase C677T (MTHRF) mutations. Women were excluded if testing was only done during pregnancy or in the immediate post-partum period.

Results:
A total of 136 women were identified. Median age was 32 (range: 18–44) with a median number of RPL of 3 (range: 2–11). Median number of first trimester losses was 2 (range 0–11). Two women had only second trimester losses and one had only third trimester losses. PS deficiency was identified in 8 women (5.8%), PC deficiency in 3 (2.2%), AT deficiency in 1 (0.7%) and APCR in 1 (0.7%). Of 30 women who had genetic analysis by PCR, 8 had abnormal results (MTHFR: 4 heterozygous, 1 homozygous; FVL: 2 heterozygous and PTG: 1 heterozygous). We did not find any correlation between the number of RPLs and the finding of a positive thrombophilia screen in the overall group or in the group of women who had molecular testing.

Conclusion:
Inherited thrombophilia is not as common in our patient population as described in other groups. However, a prospective study with a control group and a full panel of thrombophilia testing is needed to assess the prevalence and significance of such defects in women with RPL.

Disclosures:
Pathare: Sultan Qaboos University: Employment, Research Funding. Alkindi:Sultan Qaboos University: Employment, Research Funding.
PTEN Regulates Collagen-Induced Platelet Activation
Authors: Weng Zhen , Li Ding , Zhang Lin , Ruan Changgeng , Chen Guo-Qiang , Gartner T. Kent , Liu Junling 
Published: October 2019

Abstract
Abstract 5126
PI3K has been shown to play an important role in collagen-induced platelet activation, but the role(s) of PTEN, a major regulator of the PI3K/Akt signaling pathway, has not been examined in platelets. Here, we report that PTEN−/− mouse blood contains 25% more platelets than PTEN+/+ blood, and that PTEN deficiency significantly shortened the bleeding time, increased the sensitivity of platelets to collagen-induced activation and aggregation, and enhanced phosphorylation of Akt at Ser473 in response to collagen. Furthermore, we found that PP2, and the combination of apyrase, indomethcin+1B5, respectively inhibited collagen-induced aggregation in both PTEN+/+ and PTEN−/− platelets. In contrast, LY294002 (a PI3K inhibitor) prevented the aggregation of PTEN+/+, but not PTEN−/− platelets. Therefore, PTEN apparently regulates collagen-induced platelet activation through PI3K/Akt dependent and independent signaling pathways.

Disclosures:
No relevant conflicts of interest to declare.
Iron Deficiency Anemia and Chronic Renal Insufficiency In An Oncology Population
Authors: Boccia Ralph , Lahue Betsy , Hauser Robert , Dioguardi Jessica 
Published: October 2019

Abstract
Abstract 5152
Anemia in oncology patients is common and may negatively impact cancer treatment outcomes. Iron deficiency is a major contributor to anemia, which can be exacerbated by both underlying conditions and chemotherapeutic agents. Additionally, many oncology patients may have concomitant renal insufficiency or chronic kidney disease (CKD), increasing their susceptibility to iron deficiency. Therefore, recognizing renal insufficiency as well as iron deficiency may improve anemia management in oncology patients.
To determine the proportion of oncology patients with iron deficiency anemia (IDA), potential renal insufficiency and the current utilization of IV iron treatment in these populations, a large electronic medical records database was examined. All patients treated with chemotherapy in a physician services oncology network from January 1, 2008 to August 1, 2010 were selected in order to determine the prevalence of an iron deficiency anemia (IDA) diagnosis (expressed as an ICD-9-CM 280.1-.9), and a diagnosis of CKD (expressed as either from a diagnosis code of CKD (585.1-.6) or estimated GFR <60 mL/min).
Overall, 83,219 patients receiving a chemotherapeutic agent were selected. Of these patients, 36% (30,298) were diagnosed with IDA, 34% of whom were receiving IV iron treatment (9,971/30,298). These patients represented approximately 85% (9971/11,776) of the total IV iron treated population in the dataset.
While only 8% (2,482/30,298) of patients with a diagnosis of IDA also had a diagnosis of CKD. Of the patients that did present with a GFR level, 49% of patients had a GFR level <60 mL/min. However, the true prevalence of CKD in this population was difficult to determine because a significant percentage of patients did not present with a GFR level available in their records.
In this oncology patient population IDA is relatively common, with greater than 30% of patients diagnosed. While only one third of these patients were receiving IV iron treatment in the IDA patient population, it is unknown whether patients are not being treated for their iron deficiency or are being managed on oral iron therapy alone. Given recent controversies around ESA use, guidelines suggest that iron indices should be checked, and IV iron supplementation should be considered in patients receiving ESA therapy. Additionally, only a fraction of patients diagnosed with IDA are also diagnosed with CKD, even though analysis of GFR values suggests that a significant number of patients may have renal insufficiency. These data suggest that identification of patients with renal insufficiency may be suboptimal and that further treatment of IDA in this patient population may be warranted in order to optimize anemia management.

Disclosures:
Boccia: AMAG: Consultancy, Honoraria, Speakers Bureau. Lahue:AMAG: Employment. Hauser:AMAG: Research Funding. Dioguardi:AMAG: Employment.
Thrombocytopenia In Severe Anemia of Iron Deficiency
Authors: Ayalew Getinet D. , Mittal Juhi , Khillan Ratesh , Kim Miriam , Braverman Albert S. , Sidhu Gurinder 
Published: October 2019

Abstract
Abstract 5153

Introduction:
Iron deficiency suppresses hemoglobin synthesis and erythropoiesis, but the resulting anemia is frequently associated with thrombocytosis.

Methods:
The clinical and hematologic data of seven women with severe iron deficiency anemia (IDA) and thrombocytopenia were retrospectively analyzed.

Results:
All patients were African-American women with symptomatic IDA, due to bleeding from uterine fibroids in 6 and from colonic diverticulosis in 1. They were 31–70 years of age, median 38. None had palpable splenomegaly. Hemoglobin ranged from 2.9–5.5, median 4.2 g/dL. MCV ranged from 57–70 fl, median 68. Absolute reticulocyte counts ranged from 19,000 – 23, 000/mm3. The initial serum ferritin ranged from 2 to 42 ng/ml, median 4. Serum iron levels ranged from 10 to 70 mcg/dl with median 30, while iron-binding capacities ranged from 381–426 mcg/dl. Serum erythropoietin (EPO) levels were >2000U/ml in two of the patients. Serum lactic dehydrogenase, bilirubin levels and liver function tests were normal; and Coombs' test negative in all cases. White blood cell counts were normal. The platelet counts ranged from 12 to 103, with a median of 46 × 109/L. Peripheral blood smears showed microcytic hypochromic red blood cells (RBC), with no evidence of platelet clumping. Bone marrow aspiration and biopsy on two patients showed increased numbers of normal megakaryocytes, erythroid hyperplasia and absent iron stores.
Six patients were treated with packed RBC transfusions, and ferrous sulphate 325 mg orally was initiated at presentation in 7. Their thrombocytopenia was not treated with steroids or other agents. Three patients' platelet count reached normal or super-normal levels within 72 hours. Six patients were seen at ≥3 months after presentation, and all had achieved normal platelet counts and hemoglobin.

Conclusions:
These data imply that severe IDA can sometimes cause thrombocytopenia rather than thromobocytosis. We cannot be sure whether these patients' uniform normalization of platelet counts was due to treatment of their anemia by transfusion, or iron therapy. Though bone marrow megakaryocyte numbers were increased in 2 patients, there is no evidence for peripheral platelet destruction. Platelet release from megakaryocytes may have decreased in these patients. Pharmacologic EPO therapy can occasionally cause thrombocytopenia, and high endogenous EPO levels in our patients may have reduce their platelet counts. This conclusion is consistent with their apparent response to transfusion. Though the pathogenesis of IDA-associated thrombocytopenia is not known, our data suggest that the results of anemia and iron deficiency treatment should be evaluated before investigating thrombocytopenia as an independent problem.

Disclosures:
No relevant conflicts of interest to declare.
A T2* MRI Prospective Survey on Heart and Liver Iron In Thalassemia Major Patients Treated with Sequential Deferipron–Desferrioxamine versus Deferasirox
Authors: Pepe Alessia , Rossi Giuseppe , Meloni Antonella , Maria Chiara Dell'Amico , Domenico Giuseppe D'Ascola , Capra Marcello , Filosa Aldo , Cianciulli Paolo , Maggio Aurelio , Salvatori Cristina , Restaino Gennaro , Lombardi Massimo , Borgna-Pignatti Caterina 
Published: October 2019

Abstract
Abstract 5165

Introduction:
Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. No data are available in literature about possible different changes in cardiac and liver iron in TM patients treated with sequential deferiprone–deferoxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO vs DFX in a cohort of TM patients by quantitative MR.

Methods:
Among the first 739 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 253 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 25 patients treated with DFP-DFO versus the 44 patients treated with DFX between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique.

Results:
The doses of the sequential treatment were DFP 70±14 mg/kg/d for 4 d/w and DFO 42±8 mg/kg/d for 3 d/w, the dose of DFX was 26±6 mg/kg/d. Excellent/good levels of compliance were similar in the 2 groups (DFP-DFO 96% vs DFX 100%; P = 0.36). At baseline the 2 groups were homogeneous for cardiac and liver iron. Among the patients with no significant myocardial iron overload at baseline (global heart T2* 3 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% vs DFX 96%; P = 1.0). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only in the DFX group there was a significant improvement in the global heart T2* value (11 ± 5 ms at baseline versus 16 ± 8 at 18 ± 3 months, P = 0.0001) and in the number of segment with a normal T2* value (P = 0.003). The improvement in the global heart T2* was not significantly difference in the DFP-DFO versus the DFX group (mean difference global heart T2* 2.2 ± 4.1 ms versus 4.6 ± 4.8 P = 0.2). The changes in the mean serum ferritin level were not significantly different between groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant between groups (mean difference liver T2* 0.9 ± 2.1 ms vs 2.4 ± 5.2; P = 0.3).

Conclusions:
Prospectively in the clinical setting over 15 months we did not find significant differences on cardiac and liver iron by quantitative MRI in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFX.

Disclosures:
No relevant conflicts of interest to declare.
Precision of Multi-Echo CMR for Myocardial Iron Overload Evaluation Is Dependent From MR Sequence Design
Authors: Meloni Antonella , Positano incenzo , Pepe Alessia , Maria Chiara Dell'Amico , Menichetti Luca , De Marchi Daniele , Favilli Brunella , Peluso Angelo , Spasiano Anna , Landini Luigi , Maggio Aurelio , Lombardi Massimo 
Published: October 2019

Abstract
Abstract 5169

Introduction.
T2* multiecho cardiovascular magnetic resonance (CMR) is largely used to assess iron overload in heart because of the established inverse relationship between the T2* value and the iron concentration in tissues (Wood JC et al, Hemoglobin 2008). The decay of CMR signal is sampled at several echo times (TEs) and the T2* is inferred by fitting the decay curve to an appropriate model (Positano V et al, NMR in Biomed 2007). Our aim was to quantify the reliance on TEs of the expected error in T2* value determination.

Methods.
The Cramer-Rao lower bounds theory (CRLB) was used. CRLB provide a fundamental limit to the accuracy in determination of the T2* value from experimental data in dependence of SNR at signal samples. CRLB were evaluated for a commonly used multi-echo sequence with the first TE equal to the minimum achievable (1.4-2 ms), ΔTE of about 2.3 ms to minimize the fat-water interface artifacts, 10 echoes to assure acquisition in a single breath-hold.

Results.
Percent error in T2* values assessment was lower than 10% in the range of clinical interest, with the exception of very low T2* values. Precision in measurement of low T2* values is strongly dependent on the value of the first TE, that is limited by the used scanner. T2* values greater than 1.8 ms and 1.5 ms can be assessed with an error below 20% using a first TE of 2 ms and 1.5 ms, respectively (see Figure).

Conclusions.
T2* multiecho sequences used in clinical practice assure an acceptable precision for T2* values ≥ 2 ms, depending from the used hardware. This limit includes almost all patients with hemochromatosis or hemosiderosis in country where the patients can be well managed. For patients with very high myocardial iron overload sequences with lower minimum echo time and/or lower echoes interval may be useful.

Disclosures:
No relevant conflicts of interest to declare.
Study of Two Subjects with Absence of Severe Anemia with Homozygous β0 Thalassemia Due to Disrupted γ-to-β Switch
Authors: Yoon Donghoon , Kim Soo Jin , Hickman Kimberly , Hussey Dottie , Prchal Josef T. 
Published: October 2019

Abstract
Abstract 5172
Sickle cell disease (SCD) and β thalassemia due to defects of the HBB (β globin gene) are among the most common inherited genetic disorders. At birth, there is a switch of γ globin transcription to β and d, with replacement of HbF by HbA and HbA2 virtually completed by six months of age. At that time, serious inherited disorders of the β gene, such as sickle cell disease and Cooley's anemia (homozygosity for β0 thalassemia mutations), become clinically apparent. Cooley's anemia is a life-threatening disorder wherein, in most patients, chronic transfusions or bone marrow transplantations are needed to sustain life. Rare patients with homozygosity or compound heterozygosity for β0 have no or only mild anemia. These patients maintain a high level of γ globin synthesis, apparently from a disrupted γ-to-β switch, thus attenuating their disease state. Recent work has demonstrated that BCL11A plays an important role in the suppression of γ-globin expression, as do polymorphisms of the gene that remain to be fully elucidated at a functional level. We recruited two unrelated subjects with homozygous β0 thalassemia mutations with no or only mild anemia (Patient #1, IVS2+1 G>A; Hb 14.2 Gm%; 97.2% HbF, 2.8% HbA2, Patient #2, IVS 2 G-T; Hb 11.2 Gm%; 92/5% HbF, 6.8% HbA2, 0.7% HbA). We sequenced transcripts and genomic loci of BCL11A from these patients. No mutations or splicing variants on transcripts were found. However, when the ≂f102 kb of genomic material from patient #1 was sequenced, 5 single nucleotide changes at intron II were found (2 known and 3 previously unpublished), while no genomic changes were found in patient #2. We then performed in vitro erythroid expansion from peripheral blood utilizing high erythropoietin concentrations and analyzed the cell proliferation and expression of globin and BCL11A genes. Interestingly, detectable amounts of β-globin transcripts were present in both patients during expansion, although protein levels were not detectable by the conventional HPLC method, probably due to limited sensitivity of this assay. Patient #1 showed mild in vitro induction of β-globin expression, which is lower than the control group, but no apparent cell proliferation. Patient #2 showed no induction of β-globin expression and hyperproliferation at a later stage of expansion (See Figure); however, the levels of BCL11A and γ-globin transcripts were indistinguishable from controls.
Although we were unable to detect any abnormality of the BCL11A transcript as a cause of high fetal hemoglobin expression in these patients, we cannot rule out the possibility that the intronic mutations in patient #1 may interfere with BCL11A gene translation, perhaps by interference with non-coding RNA. The potential molecular mechanism of γ-to-β switch is being explored by gene expression profiling and microRNA analyses.

Disclosures:
No relevant conflicts of interest to declare.
Differential Modulation of Cytokines by VEGF In End Stage Renal Disease
Authors: Bansal Vinod , Hoppensteadt Debra , Litinas Evangelos , Thethi Indermohan , Fareed Jawed 
Published: October 2019

Abstract
Abstract 5187
Vascular endothelial growth factor (VEGF) mediates nitric oxide dependent angiogenic effects contribute to the inflammatory responses. VEGF is upregulated in ESRD and contributes to the cardiovascular dysfunction in ESRD. VEGF is also upregulated by erythropoietin which is commonly used in the management of ESRD patients. With the availability of BioChip Array Technology, a multiparametric screening of inflammatory mediators/cytokines can be measured and relevance of VEGF can be established. Utilizing the Randox Biochip technology, we profiled the plasma samples from 53 ESRD patients to determine their relevance to VEGF levels. Pre-dialysis samples from 53 male and female ESRD patients on maintenance hemodialysis were analyzed using a cytokine biochip for VEGF, IL2, IL4, IL6, IL8, IFNG1, TNF, IL1, MCP-1 and EGF. In addition, NO, asymmetric dimethyl arginine (ADMA), serotonin and functional microparticles levels were also measured. A group of 50 normal healthy males and females constituted the control group. The circulating levels of VEFG and mediators were compared with the normals. In addition, VEGF levels were compared with the other mediators. In comparison to the normals, ESRD patients exhibited decreased levels of IL4, IL8, TNF and EGF, which ranged from 20–210%. Increased levels of IL2, IL6, IL10, IFNG1, IL1 and MCP-1 were noted (20-350%). NO levels were also increased, however ADMA remained unchanged. Both the serotonin and microparticle levels were also elevated in comparison to the normals (p>0.05) VEGF levels showed wide variation, however on a cumulative basis a 30–210% increase in VEGF was noted. Except for the MCP-1, the correlation of VEGF with other inflammatory markers was relatively poor (r2=<0.25). These results show that ESRD patients can be profiled for various inflammatory mediators. VEGF levels were markedly increased, however only MCP-1 levels correlated well with the increase in VEGF levels. Additional studies are warranted to clarify the regulatory role of VEGF and other mediators on inflammatory cytokines and cellular activation in ESRD.

Disclosures:
No relevant conflicts of interest to declare.