bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fut2
−/− (Non-Secretor) Mice Exhibit High Vwf Levels.
Authors: Johnsen Jill M. , Yohannes Ermias , Walsh Thomas W 
Published: October 2019

Abstract
Abstract 2184
Levels of the critical adhesive glycoprotein von Willebrand Factor (VWF) are widely variable in human populations. Two-thirds of VWF variation is heritable, of which one-third is due to the carbohydrate blood group ABO. Another closely related carbohydrate blood group, Secretor (FUT2), has also been reported to influence VWF levels, but this association is controversial. In humans, FUT2 nonsense mutations are common and result in the loss of FUT2 enzyme activity and the absence of Lewis and ABH sugars in mucosal secretions, hence the designation of FUT2 null individuals as “non-Secretors”. The FUT2 (Secretor) fucosyltransferase makes H antigen (fucalpha1à2betagal) in mucosal tissues, which can subsequently be fucosylated by other Lewis enzymes (FUT3, FUT6, etc.) to generate the variations within the Lewis blood groups system, or serve as a substrate for the ABO glycosyltransferase to generate ABH structures. To investigate the hypothesis that Secretor influences VWF, we examined Vwf levels in Fut2 knock-out (non-Secretor) mice. The Fut2 knock-out mouse line backcrossed >20 generations to C57BL6/J was recovered from cryopreserved stock at the Jackson Laboratory. Eight to 12 week old male mice were selected for study to avoid the potential effects of estrous and aging on Vwf levels. Platelet-poor plasma was obtained from Fut2−/− (non-Secretor, n=7) and their Fut2+/+ (Secretor, n=5) littermates and assayed for Vwf antigen (Vwf:Ag) by sandwich ELISA using polyclonal anti-VWF antibodies [rabbit anti-human VWF (Dako); sheep anti-human VWF (Abcam)] and a pooled C57BL6/J plasma standard. Non-Secretor (Fut2−/−) animals exhibited Vwf:Ag levels nearly double those of their Secretor (Fut2+/+) littermates (p<0.01, Table 1). These data show that Secretor (Fut2) plays a significant role in VWF homeostasis in mice, consistent with previous reports suggesting that human Secretors have lower VWF levels than non-Secretors. We speculate that the large effect size of Fut2 on Vwf:Ag observed in this study is due to the absence of the confounding effects of variation in ABO and vascular H expression common amongst humans. Though Fut2 is expressed primarily at mucosal surfaces, FUT2-derived H antigen is thought to be transferred to red cells via adsorption of glycolipids. This work offers new clues into the complexities of VWF homeostasis by implicating carbohydrate-dependent mechanisms other than those of classical intracellular ER-golgi post-translational glycosylation as a means to influence VWF.
Vwf:Ag (+/− 1SD) Secretor (Fut2+/+) 103 +/− 39 Non-Secretor (Fut2−/−) 196 +/− 65 p=0.01, Student's unpaired two-tailed ttest.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Features of Severe Acquired ADAMTS13 Deficiency in Thrombotic Thrombocytopenic Purpura: Second Report of the Korean TTP Registry.
Authors: Oh Doyeun , Jang Moon Ju , Kim Inho , Bang Soo-Mee , Jung Chul-Won , Lee Jong-Wook , Eom Ki-Seong , Lee Hong Ghi , Kim Yeo-Kyeoung , Kim Byung Soo , Kim Jin-Seok , Lee Young , Yhim Ho-Young , Sohn Sang Kyun , Yoon Hwi-Joong , Jang Seongsoo , Jo Deog-Yeon , Cho Goon Jae 
Published: October 2019

Abstract
Abstract 2188
The clinical utility of ADAMTS13 activity for TTP has been extensively studied for last years. However, the clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is still unclear. We previously reported the characteristics of severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and patients with severe ADAMTS13 deficiency had lower serum creatinine levels than patients with non-severe ADAMTS13 deficiency using 66 patients enrolled from January 2005 to December 2008. (Jang MJ et al, Int J Hematol 2011;93:163–9). In this second report, we enrolled 65 additional patients from January 2009 to June 2012 and analyzed 131 TTP patients using same methods. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001), lower platelet counts (P<0.0001), and high total bilirubin levels (P=0.018) at presentation. However, as same as previous results, treatment outcomes did not differ significantly between severe and non-severe ADAMTS13 deficiency groups in response rate (82 vs. 65%, P = 0.256), remission rate (70 vs. 63%, P = 0.781), and mortality rate (23 vs. 18%, P = 0.820). After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. In conclusion, although TTP with severe ADAMTS13 deficiency is a unique subgroup characterized by lower platelet count and relatively good renal function, the prognostic significance of ADAMTS13 is still unclear and further study would be required to clarify it.

Disclosures:
No relevant conflicts of interest to declare.
Preclinical Efficacy Testing of Baxter's Recombinant ADAMTS13 in a Mouse Model of TTP.
Authors: Schiviz Alexandra , Resch Marlene , Farnleitner Elisa , Rottensteiner Hanspeter , Scheiflinger Friedrich , Schwarz Hans Peter , Hoellriegl Werner , Muchitsch Eva-Maria 
Published: October 2019

Abstract
Abstract 2216
Baxter is currently developing a recombinant ADAMTS13 (rADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) product for potential prophylaxis and treatment of thrombotic thrombocytopenic purpura (TTP). We established a disease model in ADAMTS13 ko mice (B6.129-ADAMTS13tm1Dgi), in which the animals simultaneously and consistently develop TTP-like symptoms by challenge with a high dose of human recombinant von Willebrand factor (rVWF) containing ultra-large VWF multimers.
To test the prophylactic efficacy of Baxter's rADAMTS13, groups of 10 ADAMTS13 ko mice received single doses of rADAMTS13 (1, 5, 40, 80 or 200U/kg) before challenge with rVWF. Doses of 1 and 5mL/kg fresh frozen plasma corresponding to 1 and 5U/kg ADAMTS13 served as positive controls. In a second study, the prophylactic and therapeutic efficacy of Baxter's rADAMTS13 was tested over time. Groups of 10 ADAMTS13 ko mice received a single dose of 200 FRETS-U/kg rADAMTS13 5min-120h before, or 15–180min after challenge with rVWF. In both studies, buffer was used as a negative control. Efficacy was defined as the degree of prevention of platelet drop and LDH increase. Schistocytosis and organ damage were also assessed.
Morbidity in negative controls was 100%: all animals receiving rVWF containing ultra-large VWF multimers were severely thrombocytopenic, showed increased LDH levels, schistocytosis and organ damage.
Prophylactic treatment with rADAMTS13 prevented LDH increase (p<0.0001), and dose-dependently prevented thrombocytopenia (p≤0.0003), schistocytosis and alleviated organ damage compared to treatment with buffer.
Efficacy of rADAMTS13 was treatment interval-dependent in both studies. Platelet count at termination of all rADAMTS13-treated animals was statistically higher than that of buffer-treated controls (p≤0.0001). However, animals receiving prophylactic treatment 120h before administration of rVWF showed severe thrombocytopenia; clinically relevant protection was only seen with treatment intervals ≤72h. Therapeutic treatment with rADAMTS13 stabilized platelet count and prevented further thrombocytopenia. LDH, schistocytosis and organ damage confirmed the treatment interval-dependent improvement in platelet count.
In summary, Baxter's rADAMTS13 was effective in an rVWF-induced animal model closely mimicking the situation in patients with hereditary TTP. Comparison with FFP, the current standard of treatment of TTP, showed Baxter's rADAMTS13 to have similar or slightly improved efficacy.

Disclosures:
Schiviz: Baxter Innovations GmbH: Employment. Resch:Baxter Innovations GmbH: Employment. Farnleitner:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.
Structural Characterization of Baxter's Recombinant Human ADAMTS13 Drug Candidate.
Authors: Foettinger-Vacha Alexandra , Kaliwoda Martin , Matthiessen Peter , Hasslacher Meinhard , Rottensteiner Hanspeter , Turecek Peter L , Mitterer Artur , Scheiflinger Friedrich 
Published: October 2019

Abstract
Abstract 2236
Baxter has developed a human recombinant (r) ADAMTS13 for treatment of patients with hereditary TTP. The protein is produced in a CHO cell-line using serum and protein-free fermentation technology. The purification process does not use immune-affinity chromatography, and includes two viral reduction steps. The final drug product is formulated without proteins of animal or human origin.
Here we characterize preclinical and clinical lots of rADAMTS13 with respect to their structural properties. The molecular weight of rADAMTS13 was determined by MALDI TOF as ∼173 kDa. SDS-PAGE showed one band at ∼190 kDa; no additional distinct protein bands corresponding to other proteins or product related degradation products were visible in the gels. Investigation of the primary structure of rADAMTS13 by peptide mapping revealed a sequence coverage of 98% compared to the theoretical amino acid sequence, and no peptides from the signal or propeptide. Peptide mapping was also used to determine posttranslational modifications of rADAMTS13. Seven O-glycosylation sites were identified in addition to the predicted N-glycosylation, O-fucosylation and C-mannosylation sites. The relative monosaccharide and N-linked oligosaccharides composition was consistent in all preclinical and clinical rADAMTS13 batches. The main N-glycan structure found on rADAMTS13 is a biantennary, core fucosylated complex type oligosaccharide with one or two sialic acids. Quantification of sialic acid determination showed consistent amounts of sialic acid on the terminal ends of the glycans in preclinical and clinical rADAMTS13 samples. N-glycolylneuraminic acid, a potentially immunogenic variant of sialic acid, was <1% the amount of total sialic acids.
Higher order structure analysis using dynamic light scattering showed a similar hydrodynamic diameter for all preclinical and clinical lots. Finally, FT-IR and CD analysis showed comparable amounts of α-helix and β-sheet in preclinical and clinical lots.
Taken together, similarity was shown between the preclinical and clinical lots of rADAMTS13 in all assays. A phase I clinical trial using rADAMTS13 for the treatment of hereditary TTP patients is expected to start soon.

Disclosures:
Foettinger-Vacha: Baxter Innovations GmbH: Employment. Kaliwoda:Baxter Innovations GmbH: Employment. Matthiessen:Baxter Innovations GmbH: Employment. Hasslacher:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Mitterer:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.
Effects of Multiple Myeloma (MM) Therapy and Type of Thromboprophylaxis On the Incidence and Timing of Venous Thromboembolism (VTE) and Factors Predictive of VTE.
Authors: Shah Jatin J. , Hegde Aparna , Zhou Xiao , Thomas Sheeba K. , Wang Michael , Weber Donna M. , Alexanian Raymond , Orlowski Robert Z. , Vadhan-Raj Saroj 
Published: October 2019

Abstract
Abstract 2244

Background:
Patients (pts) with MM are at increased risk for VTE due to various risk factors related to the host, disease, and treatment. Immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide have further increased the risk of VTE. Several studies have shown the VTE risk can be reduced with the use of low molecular weight heparin (LMWH) or aspirin thromboprophylaxis. Based on these findings, VTE thromboprophylaxis has been recommended in pts receiving IMiDs + Dexamethasone (Dex), but the impact of these guidelines on patient outcomes in clinical practice is unclear. The objective of this observational study was to evaluate the incidence, timing and risk factors of VTE and the impact of different types of thromboprophylaxis on the incidence of VTE.

Methods:
This was a retrospective cohort study, and included all MM pts newly referred to the M.D. Anderson Cancer Center in 2006. Medical records of these pts were reviewed for the type and site of VTE, the incidence and timing of VTE during the five-year period from the referral date, and the risk factors, including pt demographics, co-morbidities, baseline laboratory values, types of MM and treatment, and types of thromboprophylaxis. Univariate and multivariate proportional hazard models were fitted to find the independent risk factors predictive of VTE. The stepwise selection method was employed to build a multivariate model using variables with p<0.15 in univariate analysis.

Results:
The cumulative incidence of VTE was 24% (38/159 pts) during the 5-year follow up period. Of the 38 pts with VTE, 25 (66%) had deep vein thrombosis (DVT), 11 (29%) had pulmonary embolus (PE), and 2 had concurrent DVT and PE. Most of the pts (32/38, 84%) had VTE within 1 year from the referral date. The incidence of recurrent VTE among these pts was 27.5% (11/38 pts), for a total of 52 episodes. Since the majority of VTEs and recurrences were within one year, we examined the risk factors for VTE during this period. Treatment with IMiDs + Dex and thromboprophylaxis with LMWH or Coumadin were independent predictive factors as shown below.
The incidence of VTE was highest in pts exposed to IMiDs + Dex (30/38 pts), even after discontinuation of treatment, with most episodes (17/30) occurring during the preparation (7/30) or within 30 days (10/30) following hematopoietic stem cell transplantation (HSCT), when most (16/17) pts were not receiving anti-coagulants.

Conclusions:
These findings suggest that patients treated with IMiDs + Dex are at high risk for VTE, even after discontinuation of this treatment, especially, during and after the HSCT period. Future studies are needed to investigate VTE prevention strategies for this high-risk pt population.

Disclosures:
No relevant conflicts of interest to declare.
Simvastatin Improve ADAMTS13 mRNA and Protein Expression in Podocytes.
Authors: Shen Lei , Lu Guoyuan , Dong Ningzheng , Ma Zhenni , Ruan Changgeng 
Published: October 2019

Abstract
Abstract 2246

Aim:
ADAMTS13 is a specific VWF (von Willebrand factor) -cleaving protease, which severe deficiency is the main cause of thrombotic thrombocytopenic purpura. ADAMTS13 is mainly synthesized and released of the surface of hepatic stellate cells and endothelial cells, but is alsoexpressed in other cells, including kidneypodocytes. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, not only has benefit action on atherosclerosis but also has anti-inflammatory and antithrombotic properties. Recent study indicated that ADAMTS13 can reduce inflammatory plaque formation during early atherosclerosis in mice. In this study, we investigate the effects of simvastatinon inflammatory factors-induced ADAMTS13 expression in podocytes.

Methods:
A conditionally immortalized mouse podocyte cell line was used in the study. Inflammatory factors (TNF-Á, IL-4, IL-6) and simvastatin were added to cell culture medium to exam their effect on ADAMTS13expresion in podocytes. We examedADAMTS13mRNA and protein expressbyquantitative real-time PCR (qRT-PCR) and Western blotting.

Results:
Our results showed that ADAMTS13 mRNA and protein was expressed in podocytes, and its expression levels were significantly decreased in cells treated withdifferent concentrations of IL-4 (1, 5,10 ng/mL) and IL-6(1,10, 100 ng/mL), while TNF-Á almost had no effect on ADAMTS13 expression. When podocytes treated with simvastatin (1 and 10 Ìmol/L), ADAMTS13 mRNA were significantly increased (1.53 ± 0.80 and 3.46 ±1.70, respectively, p<0.01 vs control), and ADAMTS13 protein levels were also increased (2.05 ± 0.18 and 2.22±0.12, respectively, p<0.01 vs control). Simvastatin also can reverse the inhibition effect of IL-6 (100 ng/mL) and IL-4 (10 ng/mL) on ADAMTS13 mRNA and protein expression in podocytes in a dose-independent manner.

Conclusions:
We demonstrate that different inflammatory cytokines had different influence on ADAMTS13's expression in podocytes. Simvastatin can increase the expression of ADAMTS13 in a dose-dependent manner with or without IL-6 and IL-4, which may be a very relevant compartment for the antithrombotic property of simvastatin.

Disclosures:
No relevant conflicts of interest to declare.
Trends in the Incidence of Venous Thromboembolism Adjusted for Body Mass Index (BMI).
Authors: Kevin Cohoon P. , Ashrani Aneel A. , Petterson Tanya M. , Crusan Daniel J. , Bailey Kent R , Heit John A 
Published: October 2019

Abstract
Abstract 2256

Background:
The incidence of venous thromboembolism (VTE) may be increasing due to the obesity epidemic.

Objective:
To estimate the incidence of VTE and describe trends in incidence adjusted for the population's increase in BMI.

Methods:
Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis (DVT) or pulmonary embolism (PE) over the 13-year period, 1988–2000 (n=1,400). Age and BMI at VTE diagnosis and gender were collected for all cases. Age was categorized into 10 year intervals. Using a model for the population distribution of BMI derived from several (n=6) non-VTE Olmsted County cohorts (n=8,011 individuals), we calculated the probability of falling into each of five BMI categories (<18.5, 18.5–24, 25–29, 30–34, 35+) for each age, gender and calendar year. In Olmsted County in the median age group, the prevalence of BMI >30 kg/m2increased from approximately 15% in 1980 to 36% in 2000. We applied these probabilities to the decennial census data for 1980, 1990, 2000 using linearly interpolated census values for intra-census years to obtain Olmsted County age/sex/calendar year/BMI category denominators. Generalized linear modeling assuming a Poisson error structure, and using a log link function, and a log (population) offset was used to assess the relationship of crude incidence rates to gender, year of diagnosis, age and BMI.

Results:
The overall average age- and sex-adjusted annual VTE incidence was 120 per 100,000 person-years (DVT: 66 per 100,000; PE: 54 per 100,000), with higher age-adjusted rates among men than women (129 versus 113 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 3 to 1,079 per 100,000 for age groups 0–19 to 90–110 years. Age and sex-adjusted VTE incidence increased by increasing BMI category (88, 112, 106, 150, and 195 per 100,000 person-years, respectively, by increasing BMI category). Unadjusted for BMI, VTE incidence was unchanged from 1988 through 2000 (p=0.70). After adjusting for age, gender and calendar year, VTE incidence increased with increasing BMI (p<0.0001). The calendar year incidence slope estimate decreased numerically from 3% per decade to minus 4% per decade after adjusting for increasing BMI, remaining nonsignificant (p=0.57).

Conclusions:
VTE remains a major national health problem, especially among the obese. Despite the dramatically increasing population BMI, and the significant association of BMI category with VTE incidence, the overall incidence of VTE remained unchanged over the timeframe, 1988–2000.

Disclosures:
No relevant conflicts of interest to declare.
Real Life Efficacy and Safety of Rivaroxaban for Extended VTE Treatment – First Results of the Prospective Noac Registry (NCT01588119).
Authors: Koehler Christina , Werth Sebastian , Gelbricht Vera , Haensel Ulrike , Tittl Luise , Beyer-Westendorf Ines , Schreier Thomas , Eulitz Maria , Beyer-Westendorf Jan 
Published: October 2019

Abstract
Abstract 2267

Background:
In the EINSTEIN-EXT trial, rivaroxaban (RX) has been found to be at least as effective and safe as warfarin in extended venous thromboembolism (VTE) treatment, which lead to approval in many countries. However, patients in RCT‘s present a selected population treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care.

Objectives:
To evaluate the efficacy, safety and management issues of rivaroxaban anticoagulation for extended VTE treatment in daily care.

Patients and methods:
In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data.

Results:
Until July 31th 2012, 938 patients were registered. Of these, 126 patients received RX for extended VTE treatment (demographic data in table 1). In our registry, the population receiving extended VTE treatment is older than in EINSTEIN-EXT (65.0 vs. 58.2 years). Indication for prolonged treatment is proximal deep vein thrombosis or pulmonary embolism (93.3%). Most patients received 20 mg OD, but a quarter of patients received 15 mg OD due to impaired renal function.
Until July 31th, completed FU cumulate to 44.2 patient years. The results of 1-, 3- and 6-months FU are shown in table 2. Until now, no recurrent VTE or VTE-related death occurred. Two patients experienced major vascular events (1 ACS, 1 TIA). Bleeding events were frequent (24.6%) but only 2 patients (1.6%) experienced major bleeding events, none of which were fatal. Two patients died due to underlying diseases. At 3 and 6 month, 94% resp. 85% of patients were still taking RX.

Conclusion:
In unselected patients in daily care, extended VTE treatment with RX is effective and safe with low rates of events or treatment discontinuation in the first 180 days of treatment. Long-term data will be reported.

Disclosures:
Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.