bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic Differences of An Anti-Xa Enriched Low Molecular Weight Heparin, AVE 5026 in Comparison to Enoxaparin and Unfractionated Heparin.
Authors: Hoppensteadt Debra , Gray Angel , Litinas Evangelos , Kaiser Brigitte , Fareed Jawed 
Published: October 2019

Abstract
Abstract 4171
AVE5026 (Sanofi-Aventis, Paris, France) represents an anti-Factor (F) Xa enriched ultra low molecular weight heparin (ULMWH) (Mw=2.4 Kda; anti-FXa activity ∼160 U/mg). In comparison to Enoxaparin it has a lower anti-FIIa activity (∼2 U/mg). The oligosaccharide composition of AVE5026 also differs from Enoxaparin and other LMWHs. Besides the molecular and compositional differences, the biologic half-life of AVE5026 (18-20 hours) is significantly longer than Enoxaparin (4-6 hours). In order to compare the other pharmacodynamic differences between AVE5026, Enoxaparin and unfractionated heparin (UFH), a primate model (macaca mulatto) was used since its tissue factor pathway inhibitor (TFPI) profile is comparable to the human response. Individual groups of primates (n=6) were administered with 1 mg/kg SC of either AVE5026, Enoxaparin or UFH. Heptest and APTT measurements were determined on whole blood (WB) and plasma was analyzed for APTT, Heptest, thrombin time (TT), anti-FXa and anti-FIIa effects at varying periods up to 28 hours. TFPI antigen was measured using the assay from Stago (Parsipanny, NJ). Functional TFPI measurements were determined using the kit from American Diagnostica (Stamford, CT). In contrast to UFH, in the WB assays, neither the AVE5026 nor the Enoxaparin produced a strong effect on the APTT and TT, however both demonstrated a strong effect on the heptest assay. AVE5026 produced a much stronger effect with a longer half-life (T½=11 hrs) in comparison to Enoxaparin (T½=6 hrs). In the plasma based systems only UFH produced a measurable effect on the APTT and TT. However, in the heptest and anti-FXa assays, both AVE5026 and Enoxaparin produced a stronger effect, which was much longer with AVE5026 (2-3 fold increase). The plasma time course of TFPI antigen release was longer with AVE5026 in comparison to Enoxaparin and UFH. The ratios of immunologic to functional TFPI levels were also higher in the primates administered with AVE 5026. In the thrombin generation test, AVE5026 produced a sustained effect which lasted longer than Enoxaparin (T½ =16.8 hrs vs. 9.2 hrs.). These results show that AVE5026 produces stronger anti-FXa effects in primates which are associated with a higher circulating level of TFPI and more pronounced suppression of thrombin generation compared to Enoxaparin and UFH.

Disclosures:
Hoppensteadt: Sanofi-Aventis: Research Funding.
Combination of FXI Antisense Oligonucleotide and Plavix® Treatment Results in Enhanced Antithrombotic Activity without Increased Risk of Bleeding in Mouse Models of Thrombosis.
Authors: Gao Dacao , Crosby Jeff , MacLeod Robert , Bhattacharjee Gourab , Lowenberg Ester C , Levi Marcel , Monia Brett P. 
Published: October 2019

Abstract
Abstract 4173
Factor XI (FXI) is a serine protease produced in the liver that contributes to thrombin generation via the intrinsic coagulation pathway. Also, it is a key component of an amplification pathway that is thought to sustain thrombin production at a wound site to maintain fibrin clot integrity. Loss of function mutations in the human FXI gene results in FXI deficiency, a disorder which is associated with only mild bleeding. In addition, high levels of FXI are a risk factor for thrombosis. We have previously presented the antithrombotic efficacy and safety of antisense oligonucleotide (ASO) mediated FXI depletion in various animal models of thrombosis. We have demonstrated that in combination with Lovenox®, FXI ASO treatment increases antithrombotic activity but does not increase bleeding risk. The purpose of the current study was to evaluate the relative risk/benefit of ASO mediated Factor XI depletion in combination with the platelet antagonist Plavix®. The “risk” component was bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was antithrombotic effect in arterial and venous mouse models of thrombosis. Our study investigated a 20 mg/kg dose of FXI ASO in combination with a dose response of Plavix® and indicates that antisense mediated FXI depletion provides enhanced antithrombotic protection when given in combination with Plavix®. The combination of FXI ASO and Plavix® did not result in increased bleeding tendency. In contrast, treatment with a small molecule inhibitor of factor Xa in combination with Plavix® significantly increased bleeding. The approach used in this study is being used to define the ability of FXI ASO to combine with standard of care agents for the treatment of thrombosis.

Disclosures:
Gao: Isis Pharmaceuticals, Inc.: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. MacLeod:Isis Pharmaceuticals: Employment. Bhattacharjee:Isis Pharmaceuticals, Inc.: Employment. Lowenberg:Isis Pharmaceuticals, Inc.: Consultancy. Levi:Isis Pharmaceuticals, Inc.: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment.
Stability of the INR in Relation to Personality Traits in Patients On Stable Oral Anticoagulant Therapy.
Authors: Harenberg Job , Weiss Christel , Felten Marie-Theres , Frölich Lutz 
Published: October 2019

Abstract
Abstract 4178
Maintenance of a stable anticoagulation as determined by the international standardized ratio (INR) remains difficult despite increasing knowledge on genetic variations of metabolism and improved therapeutic approaches. We hypothesised that personality traits of patients may influence the stability of the INR, obtained during stable therapy with vitamin-K antagonist (VKA). We assumed that the standard deviation (SD) of the INR over a time period of 6 months represents the stability of the anticoagulant treatment.
Patients (n=28) treated with VKA for more than one year in our outpatient care unit, completed a widely used personality inventory (Freiburger Persönlichkeitsinventar, FPI-R) and a questionnaire referring to general health and quality of life (SF12). Correlations between factors of FPI-R and SF12 with the standard deviation (SD) of the INR were analysed by means of the spearman correlation coefficient.
76% of all INRs of the patients were within the therapeutic range of 2 to 4 and the SDs of the patients INRs ranged from 0.23 to 1.17. The higher the social competence (FPI-R) of a person the lower was the SD of the INRs (p=0.0003). The less calm and relaxed a person felt in the past (SF12), the lower was the SD of the INRs (p=0.013). No other personality dimensions or domains of the SF-12 correlated with the variance of the INRs.
A high social competence and low score of a person feeling calm and relaxed leads to a more stable anticoagulation of patients treated with VKAs. The first finding may relate to subjects with good cooperation and social responsibility resulting in a stable anticoagulant therapy. Patients who feel troubled and worried by higher variations of INR values may cause the second finding. The data suggest that personality traits play a role for reaching a stable INR.

Disclosures:
Harenberg: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria; Roche Diagnostics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bayer Health Care: Consultancy, Honoraria.
Relation of Personality Traits in Patients with Oral Anticoagulant Therapy to Attitudes towards Treatment with Vitamin-K Antagonists.
Authors: Harenberg Job , Frölich Lutz , Felten Marie-Theres , Weiss Christel 
Published: October 2019

Abstract
Abstract 4183
Stable anticoagulation as determined by the international standardized ratio (INR) remains difficult despite increasing knowledge on pharmacogenetics of vitamin K antagonists (VKA) and improved therapeutic approaches. We hypothesised that personality traits of patients may influence attitudes towards treatment VKA.
Thirty patients treated with VKA for more than one year completed a widely used personality inventory (Freiburger Persönlichkeitsinventar, FPI-R) and a questionnaire referring to adherence, safety and anxiety problems during anticoagulant therapy after written informed consent. Indications for anticoagulation were venous thromboembolism (n=22) and atrial fibrillation (n=8). Correlations between FPI-R factors and items of the anticoagulant therapy questionnaire were analysed by means of the chi-square test.
Patients understanding the concept of VKA therapy and being open for modifications of the dose of VKA, they are more emotional and less excitable (p=0.008 and 0.009), respectively. Patients who felt burdened at initiation of VKA therapy were less achievement-oriented (p=0.02). Those who forget sometimes the intake of the VKA are more self-inhibited (p=0.004) and more socially oriented (p=0.007). Patients following a diet during anticoagulant therapy, are more concerned about general health (p=0.009) and are more socially orientated (p=0.05). Those who like to eat vitamin-K containing vegetables are more excitable (p=0.01). Importantly, patients being afraid of thrombotic events are more aggressive (p=0.01) and have more physical complaints (p=0.02). Those being afraid of bleeding complications, are more aggressive (p=0.046), more demanded (p=0.05) and more intraverted (p=0.004).
Personality traits appear to influence the therapy with VKA manifold. Fear of thrombotic or bleeding events during anticoagulant therapy can be identified by specific personality traits.

Disclosures:
Harenberg: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria; Roche Diagnostics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bayer Health Care: Consultancy, Honoraria.
An Old Story: Aggressive Antithrombotic Approach Reduced or Increased the Risk of Destabilization and Adverse Events: More Questions Than Answers.
Authors: Corinaldesi Giorgio , Corinaldesi Christian 
Published: October 2019

Abstract
Abstract 4185
Aggressive antithrombotic therapy with ASA, thienopyridine, GPIIb/IIIa inhbitors, eparin, and Vit.K antagonist (VKA) is used for unstable angina (UA), myocardial infarction (NSTEMI), acute coronary syndrome (ACS), stent implantation, atrial fibrillation (AF),VTE. The main findings of combination of antithrombotic drugs are their association with serious bleeding not withstanding some respectable benefit, and a great effects against thrombosis. At present the preferred approach for the long term treatment is VKA the dose should be adjusted to maintain a target INR of 2.5 (range: 2.0 to 3.0), the controversy focused in a patients with a high risk of recurrence a high intensity VKA therapy (INR: 3.1 to 4.0) although did not confirm a superiority in terms of thrombotic protection, new opportunities have emerged in the treatment of arterial thrombosis with the combinations of antithrombotic drugs (ASA 325mg every days, plus thienopyridine: ticlopidine 250mg orally twice a day, or clopidogrel / GPIIb-IIIa antagonist/ anticoagulant: VKA, LMWH, fondaparinux) with a significant inhibition of thrombosis but always a remarkable and unacceptable bleeding risk, and a narrow safety window. Question: what are the very primary strong end points (death, PE or symptomatic VTE, Myocardial infarction or stroke, recurrence!), or are the inhibition of platelet functions, of signalling pathways, of atherosclerotic process monitoring. Several trials have evaluated the role of long term anticoagulation therapy, and a high intensity anticoagulation and combination therapy with a marvel issue (by 32% to 48% reduction of the risk of relapse) but a burdensome toll of side effects (bleeding by 4.8% to 8.2%). We have studied 118 patients with a tailored therapy and individual strategies selecting the disease and comorbility, the dose, the timing, the manner, the potential validity and the variance of individual responses with a significant reduction of side effects (bleeding by 0.8% to 2.4%), and a preserved therapeutic benefit (by 34% to 44% reduction of the risk of relapse). Answers: the optimal management of antithrombotic therapy is the reduction of side events, and the mainstay of treatment is to maintain patency of the vessels, but it's not so easy, certainly the main road is to have a drug made to be measured.

Disclosures:
No relevant conflicts of interest to declare.
Frequency of Minor Blood Group Antigens Among Hispanic-American Blood Donors in Southwest Texas.
Authors: Silvey Michael , Beddard Rachel , Chen Yidong , Frei-Jones Melissa 
Published: October 2019

Abstract
Abstract 4188
The frequency of minor blood group antigens has not been described among Hispanic blood donors. A retrospective cohort study was performed using the South Texas Blood and Tissue Center (STBTC) donor database, LifeTrak. Blood donors self-identified race and ethnicity. Caucasian and Hispanic donors were eligible. Donors who did not have minor antigen testing performed were not included. The STBTC has a high proportion of Hispanic blood donors (299047/779409, 38%), who are primarily of Mexican ancestry. Minor antigen testing was performed in 10% (74140/779409) of all donors; 8% (25394/299407) of Hispanic donors and 11% (42891/392074) of Caucasian donors. Hispanic donors were significantly more like to express blood type O Rh+ than Caucasian donors (13920/25394, 55% v 14947/74140, 35%; p<0.001). The frequency of ABO and RhD blood groups were similar to those reported previously in Caucasian and Hispanic donors (Garraty, et al. Transfusion, 2004). Of the minor antigens, expression of Rh E also differed significantly between Hispanic and Caucasian donors (4706/11744, 40% v 5416/19497, 28%; p<0.001). The prevalence of the other minor antigens were more similar and are reported in Figure 1. Complete Rh haplotypes were available in 8296 Caucasian donors and 7176 Hispanic donors. The haplotype RhDce differed significantly in 36% of Caucasians and 50% of Hispanics (3022/8296 v 3589/7176). The haplotype RhDce was previously reported as most common in African-Americans at 44% (Avent, et al. Blood, 2000). Haplotype RhDCE was found in 8% of Caucasians and 10% of Hispanics (660/8296 v 643/7176); haplotype RhDcE in 16% of Caucasians and 15% of Hispanics (1354/8296 v 1041/7176); and haplotype RhDCe was found in 39% of Caucasians and 27% of Hispanics (3260/8296 v 1903/7176). Differences exist in the frequency of minor blood group antigens among Caucasian and Hispanic blood donors in Southwest Texas.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Analysis of 159 Times Acute Transfusion Reaction in Single Center.
Authors: Chen Qin-fen , Li Pei , Wang Xiao-Qin 
Published: October 2019

Abstract
Abstract 4196

Objective
Retrospective analysis of acute transfusion reactions occurred in our hospital in recent years.

Methods
Investigate all hospitalized patients who transfused various blood components from November 2006 to July 2009.

Results
During study period, there were 27,672 times transfusion with 80,112 units various blood components, mainly red blood cells(RBCs), frozen plasma(FP) and leukocyte-depleted platelets(PLTs). Acute transfusion reactions occured in 143 patients of 159 times transfusion, including febrile nonhemolytic transfusion reactions(FNHTR), allergic transfusion reactions(ATR), transfusion-related acute lung injury(TRALI), transfusion-associated circulatory overload(TACO) and hemorrhagic tendency. The 143 enrolled patients, 87male and 56female, were between the age of 16 and 94. The incidence rate of acute transfusion reaction was 0.57%, FNHTR and ATR accounted for 96.23%. Of all blood components, the incidence rates of acute reaction were 0.35%, 0.50% and 1.82% respectively in RBCs, FP and PLTs transfusions. In 159 times of acute transfusion reactions, the constituent ratios of 0∼3 times and more than 3 times transfusion were 23.27%, 18.87%, 7.55%, 4.40% and 45.91%, respectively.

Conclusion
Most of acute transfusion reactions were FNHTR and ATR. The highest incidence rate was in platelets transfusion, and the most constituent ratio was in patients who have received more than 3 times transfusion.

Disclosures:
No relevant conflicts of interest to declare.
Modulation of Prothrombinse Assembly and Activity by Phosphotidylethanolamine.
Authors: Majumder Rinku , Liang Xiaoe , Quinn-Allen Mary Ann , Lentz Barry R. , Kane William H. 
Published: October 2019

Abstract
Abstract 4207
Constituents of naturally occurring phospholipid membranes regulate the activity of the prothrombinase complex. In the present study we demonstrate that membranes containing phosphatidylcholine and phosphatidylethanolamine (PC:PE) bind factor Va with high affinity (Kd ∼10 nM) in the absence of phosphatidylserine (PS). These membranes support formation of a functional prothrombinase complex though thrombin generation at saturating factor Va concentrations is reduced approximately 60-70% compared to membranes containing 5% or more PS. The presence of PE markedly enhances the catalytic efficiency of the prothrombinase complex on membranes containing 1% PS with only modest effects on membranes containing 5% or more PS. The effect of PE on factor Va membrane binding appears to be due to direct interactions between PE and factor Va rather than to changes in membrane surface packing. Finally, we find that soluble C6PE is able to bind to factor Va (Kd ∼6.5 uM) and factor Xa (Kd ∼ 91 uM). We also show that soluble C6PE is able to stimulate formation of a partially active factor Va-factor Xa complex capable of catalyzing conversion of prothrombin to thrombin in the absence of a membrane surface. We further demonstrate that C6PE and C6PS binding sites in factor Xa are linked, as binding of one lipid enhances the binding and activity of the other. These findings provide important new insights into the role of PE in assembly of the prothrombinase complex that are relevant to understanding the activity of factor Xa on the surface of platelets particularly in the early phases of hemostasis when the concentration of PS may be limiting.

Disclosures:
No relevant conflicts of interest to declare.
Successful Treatment of Acquired Amegakaryocytic Thrombocytopenia with Rituximab: A Case Report.
Authors: Goldberg Laura R. , Glasser Lewis , Wu Tony , Shimizu Ikue , Quesenberry Peter J. , Butera James N. 
Published: October 2019

Abstract
Abstract 4223
Acquired amegakaryocytic thrombocytopenia is a rare disorder in which there is a marked decrease in bone marrow megakaryocytes leading to severe thrombocytopenia with preserved hematopoeisis in the remaining lineages. The clinical course is variable and no standardized treatment exists. Multiple cases in the literature report treatment using immunosuppressive agents including cyclosporine and antithymocyte globulin. In this case report, we describe the first successful use of rituximab in a patient with amegakaryocytic thrombocytopenia in the absence of any underlying autoimmune disorders. Our patient, an 86- year-old woman, presented with epistaxis, ecchymoses, and blood-tinged sputum. She had thrombocytopenia (platelets 6 × 109/L, MPV 8.3) with a normal hemoglobin and white blood cell count. Peripheral blood smear showed no obvious cause for thrombocytopenia. Bone marrow biopsy revealed focal lymphocytic infiltrates and severe megakaryocytic hypoplasia with nearly absent megakaryocytes. Cytogenetic and molecular analyses were normal, revealing no evidence of a clonal myelo- or lymphoproliferative disorder. The diagnosis of amegakaryocytic thrombocytopenia was made. She was started on prednisone 50mg per day. There was no significant improvement in her platelet count and she was then given IVIG without response. Repeat bone marrow biopsy showed persistent severe bone marrow hypoplasia with near absence of megakaryocytes. After 6 weeks of platelet transfusion dependence and steroids, she was tapered off her steroids and was given rituximab 375mg/m2 weekly for 4 doses. Three weeks after starting rituximab, her platelet counts began to recover and by day 37, her platelet counts normalized and remained within normal limits 12 months after treatment. This case demonstrates the possible utility of rituximab in treating patients with isolated acquired amegakaryocytic thrombocytopenia.

Disclosures:
No relevant conflicts of interest to declare.
Multi-Drug Resistance Phenotype in Myeloid Leukemia Cells Confers Radiation Resistance Via DNA Damage Sensor Uncoupling.
Authors: Seideman Jonathan H. , Scheinberg David A. 
Published: October 2019

Abstract
Abstract 4243
We have found that a stable multi-drug resistant (MDR) variant of the myeloid leukemia line, HL60, called RV+, which was selected for drug resistance in the presence of vincristine, is clonogenically cross-resistant to gamma radiation (RV+ Do= 0.81 Gy, HL60 Do = 0.49 Gy). At equal doses, these two different cell lines incurred equivalent DNA double strand breaks (DSBs) upon irradiation as measured by pulse-field electrophoresis, and showed nearly identical bulk DSB repair capacity and efficiency, suggesting that the resistence phenotype is not due to a reduction in DSBs. Interestingly, an early and proximal marker of DSBs, phosphorylation of the histone variant H2AX, is up to seven-fold lower in RV+ cells, despite equivalent bulk DNA damage. This discrepancy between physical damage and proximal signaling is accompanied by dramatically attenuated early and late G2/M checkpoint responses in RV+ cells, which require nearly 10 times the radiation dose of HL60 cells (2.0 Gy compared to 0.2 Gy) to elicit a full early G2/M check, and up to four times the dose (4.0 Gy compared to 1.0 Gy) for an equivalent late G2/M response. Consistent with decreased checkpoint stringency, up to eight time as many RV+ cells were found to be entering mitosis after radiation, with 62.7% unresolved DSBs as measured by micronuclei formation. Although HL60 had a comparable percentage of cells with unresolved breaks (72.6%), the total number of cells entering mitosis with intact nuclei was proportionally much lower. Moreover, in the same dose range, RV+ cells have a marked decrease in radiation-induced apoptosis compared to HL60, which has been shown to be an important clonogenic predictor in hematopoietic cells. As RV+ cells are 10-fold more sensitive to cytarabine-induced apoptosis, RV+ cell insensitivity is likely not due to a global anti-apoptotic phenotype. Increased clonogenic survival suggests that RV+ have partially decoupled sensing of extant DNA damage from checkpoint and apoptotic responses, possibly through downregulation of phospho-H2AX or its cognate upstream kinases. Current research seeks to determine a causal relationship between these unique radioresistance phenomena.

Disclosures:
No relevant conflicts of interest to declare.