bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and Rate of Venous Thrombosis in Medical Inpatients: the Medical Inpatients and Thrombosis (MITH) Study
Authors: Zakai Neil , Callas Peter , Repp Allen , Cushman Mary 
Published: October 2019

Abstract
Abstract 1239

Introduction:
While various government agencies mandate monitoring for in-hospital VT and use of VT prevention strategies, the incidence and risk factors for symptomatic venous thrombosis (VT) in medical inpatients has not been established in general medical populations with confirmation of the VT outcomes. In order to design effective preventive strategies, the scope of the problem must be understood in a real-world setting.

Methods:
Between January 2002 and June 2009 all cases of VT complicating medical admissions were identified using ICD-9 codes and confirmed by medical record review at a 500 bed teaching hospital in the United States. 601 control charts without VT ICD-9 codes were also reviewed. A case of VT was defined as VT occurring as a complication of medical admission (not on admission or a reason for admission) and required definitive imaging or autopsy evidence of VT. The incidence of VT was calculated using the number of admissions and the patient days in the hospital over the same time period cases were ascertained.

Results:
299 cases of VT complicated 64,034 admissions and 871 patient-years of observation. No cases of VT complicated admissions among controls. The occurrence of VT (per 1000 admissions and per 1000 patient-years, 95% CI) is presented in the Table. The overall VT incidence was 4.7 per 1000 admissions or 0.34 per patient-year. The rate was highest on the oncology service (0.65 per patient-year), intermediate on the medical service (0.38 per patient-year) and lowest on the cardiology service (0.13 per patient-year). Upper extremity DVT was common, at 91/180 (51%) of all deep venous thrombosis (DVT). There were 11/91 (12%) PEs among patients with upper extremity DVT, 22/86 (26%) PEs among patients with lower extremity DVT and 20% of patients with distal and proximal DVT had PE. VT occurred on median hospital day 5 (interquartile range 3–10).

Conclusion:
We report the incidence and rates of symptomatic VT in a general medical inpatient population. Prior studies relied on administrative databases and did not confirm all VT cases by record review. In our medical population, no systematic screening for VT occurred and diagnosis required clinical suspicion for VT; thus, rates under-estimate the burden of VT. While oncology patients did not have an increased incidence per admission, their rate of VT was higher when accounting for the time spent in the hospital. For the first time, we report the high incidence of upper extremity DVTs in medical inpatients, which is likely due to increasing use of vascular access devices. The occurrence of VT on median day 5 suggests that strategies to encourage VT risk assessment and provide VT prophylaxis on admission are important for VT prevention.

Disclosures:
No relevant conflicts of interest to declare.
Impact of Interim Hospitalizations on Risk of Venous Thromboembolism (VTE) Recurrence: A Nested Case-Cohort Study
Authors: Ashrani Aneel A. , Farmer Sara A. , Petterson Tanya M. , Bailey Kent R. , Leibson Cynthia L. , Heit John A. 
Published: October 2019

Abstract
Abstract 1241

Background:
Hospitalization (with or without surgery) is a major risk factor for incident venous thromboembolism (VTE); however, the contribution of interim hospitalization to risk of recurrent VTE is unknown.

Objective:
To estimate risk of recurrent VTE related to interim hospitalization by conducting a population-based longitudinal review of provider-linked detailed medical records.

Methods:
We performed a nested case-cohort study. The cohort consisted of all Olmsted County residents with incident VTE 1988–2000 and ≥1 day follow-up. Cases were cohort members with recurrent VTE. Subjects were followed for all interim hospitalizations and warfarin use from incident VTE until earliest of emigration, death, recurrent VTE, or 12/31/2005. Data were analyzed using Cox proportional hazards and time dependent covariates to test for the effects of interim hospitalization and prophylaxis on VTE recurrence, adjusting for gender and age at incident VTE. Analyses were limited to subjects who survived free of death and recurrent VTE for ≥ 6 months.

Results:
Of 1262 incident VTE events (cohort), there were 309 VTE recurrences (cases). We randomly sampled 272 subjects from the cohort and 163 cases. Of the random samples, 210 incident events and 83 cases survived ≥ 6 months free of death and recurrent VTE and form our analysis population. The rate of secondary (interim) prophylaxis was approximately 50% for both incident events and cases, and was not predictive of recurrence (p=0.73). Male gender and interim hospitalization were associated with increased VTE recurrence even after adjusting for age at incident VTE and use of secondary warfarin prophylaxis. The hazard of recurrent VTE was nearly 10-fold higher for subjects with interim hospitalization versus those with none (HR: 9.6; 95% CI: 6.6, 13.8); men had a 1.5-fold increased recurrence rate compared with women (HR: 1.5; 95% CI: 1.1, 2.1).

Conclusions:
Our results, for the first time, show the importance of interim hospitalization as a predictor of VTE recurrence.

Disclosures:
No relevant conflicts of interest to declare.
Association of Gene-Gene Interactions with Venous Thromboembolism (VTE): A Merged/Imputed Genome-Wide Scan/Candidate-Gene Case-Control Study
Authors: Heit John A. , Armasu Sebastian M. , Matsumoto Martha E. , Petterson Tanya M. , Rider David N. , Cunningham Julie M. , Asmann Yan W. , de Andrade Mariza 
Published: October 2019

Abstract
Abstract 1242

Background:
While bivariate interactions between Factor V Leiden, prothrombin G20201A and hereditary deficiency of antithrombin, protein C and protein S compound VTE risk, whether other gene-gene interactions are associated with VTE is largely unknown.

Objective:
To test novel gene-gene interactions for an association with VTE.

Methods:
Genome-wide scan (Illumina 660Q [557,112 SNPs]) and candidate gene (12,551 SNPs in 764 genes within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways) genotypes from 1270 non-Hispanic adults of European ancestry with objectively-diagnosed VTE (cases; no cancer, venous catheter or antiphospholipid antibodies) and 1302 controls (frequency-matched on case age, gender, race, MI/stroke status) were merged and imputed to about 2.5 million SNPs with MACH using HapMap Phase 2 (60 CEU). We tested all pairwise SNP-SNP interactions using a 2-stage procedure (fast epistasis in the first stage and age, gender, MI/stroke status and state of residence adjusted analysis using logistic regression in the second stage).

Results:
The mean ± standard deviation case and control ages were 54.4 ± 16.2 and 55.6 ± 15.8 years, respectively and 51% were female. Among 2.299×10^12 pairwise interactions tested, 900 million reached a p-value<E-06 and were be tested in the second stage. Of these, 2417, 278 and 22 SNP-SNP interactions reached p-values ≤1E-9, 1E–10, and1E-11 respectively; 121 SNP-SNP interactions reached the Bonferroni statistical significance threshold (≤5.555659E-11). The gene-gene pairwise interactions with p-values≤1E-11 were: (1) chromosome 3 open reading frame 70 (C3orf70) – short-chain dehydrogenase/reductase (SDR family) member 4 (DHRS4), (2) 1-acylglycerol-3-phosphate O-acyltransferase 4 (AGPAT4) - NIMA (never in mitosis gene a)-related kinase 6 (NEK6), and (3) TatD DNase domain containing 2 (TATDN2) – WAS protein family, member 3 (WASF3). No gene function data are available for C3orf70. DHRS4 encodes for a 3-ketosteroid reductase important for active steroid hormone regulation, AGPAT4 is important for signal transduction and lipid biosynthesis, NEK6 encodes for Nek6 which downregulates p53-induced cancer cell senescence, TATDN2 encodes a deoxyribonuclease, WASF3 encodes for a member of the Wiskott-Aldrich syndrome protein family which are key regulators of signal transduction and cytoskeletal reorganization in hematopoietic cells.

Conclusion:
Pairwise gene-gene interaction analyses suggest potential associations between VTE and novel genes for future testing in replication studies.

Disclosures:
Heit: Daiichi Sankyo: Consultancy, Honoraria.
Amount of Platelet Inhibition Produced When Initiating Aspirin Therapy: Comparison of Two Doses 81 Vs. 325
Authors: Schwartz Kenneth A. , Chivu Simona , Davis John 
Published: October 2019

Abstract
Abstract 1250

Introduction:
Patients with occlusive arterial disease are commonly treated with different daily doses of aspirin usually either 81 or 325mg. This treatment practice continues despite studies showing equal protection from future vascular events with daily aspirin doses that exceed 81mg. We evaluated the hypothesis that the amount of platelet inhibition observed 96 hours after initiating aspirin therapy with 3 daily doses of 81mg would be equivalent to that observed using a dose of 325mg.

Methods:
The amount of platelet inhibition produced when initiating daily aspirin therapy was evaluated using the slope of the platelet prostaglandin agonist (PPA) stimulated light aggregometry curve at 4 time points: time 0 before the first dose, 2 hours after the first dose, 24 hours after the first dose (just before the second dose) and 96 hours after the first dose (24 hours after the 3rd dose). After a 7 day wash out period, during which subjects were instructed not to take aspirin or other NSAIDs, the subjects repeated the study using a 325mg aspirin dose. Because of the large variation in reactivity of platelets among people, each normal subject served as their own control and the results were evaluated using a paired “t” test. We plan to have studied a minimum of 12 normal subjects by the time of the ASH meeting.

Results:
To date 6 normal subjects were studied. 96 hours after initiating aspirin therapy, 24 hours after the 3rd aspirin dose, there was no difference between the PPA slopes observed for the 81mg=36 and the 325mg=28 (p=.28). Immediate platelet inhibition observed in the 24 hours after initiating aspirin therapy was far greater with the 325mg than the 81mg dose. Two hours after the 81mg dose the PPA slope was 77 compared to the 325mg slope of 12 (p=.000). Similarly, the slopes 24 hours after initiating aspirin were 68 for the 81mg dose and 35 for the 325mg dose (p=.006). The time 0 slopes were also statistically different 81mg=91 and 325=78 (p=.024).

Conclusions:
1. Initiation of aspirin therapy with a dose of 325mg dose produces a more immediate inhibition of platelet function with maximal platelet inhibition observed 2 hours after the first dose. 2. Platelet inhibition with an aspirin dose of 81mg occurs more gradually with maximal platelet inhibition observed 24 hours after the 3rd dose at 96 hours. 3. Whether daily aspirin therapy is initiated with a daily dose of 81mg or 325mg, the amount of platelet inhibition observed 96 hours after starting aspirin therapy, 24 hours after the 3rd dose, is equivalent.

Comment:
This data supports the clinical observations that protection from future vascular events is equivalent with either 81 or 325mg daily dosing and suggests that the current practice of increasing the dose of aspirin in patients who experience a subsequent event may not be beneficial.

Disclosures:
No relevant conflicts of interest to declare.
Replacement Therapy for Minor Surgery and Invasive Procedures in Factor VII Deficiency: The STER Experience
Authors: Napolitano Mariasanta , Dolce Alberto , Ingerslev Jorgen , Giansily-Blaizot Muriel , Di Minno Matteo ND , Auerswald Guenter K.H. , de Saez Arlette Ruiz , Tagliaferri Annarita , Batorova Angelika , Caimi Teresa Maria , Chuansumrit Ampaiwan , Fernandez Maria Fernanda Lopez , Bertrand Marie-Anne , Verdy Elisabeth , Zanon Ezio , Abecassis Lien , Aronis Sophie , Siragusa Sergio , Orecchioni Assunta , Mariani Guglielmo 
Published: October 2019

Abstract
Abstract 1262

Introduction:
Surgical bleeding is among the most frequent symptoms in Factor VII (FVII) deficient patients: in an analysis by our group, post-surgical bleeding was reported in 24% of cases (Mariani G. et al. Thromb Haemost 2005;93:481). A recent retrospective study showed a similar prevalence of surgical bleeding (15%) with a significant relation between this type of bleeding, deep hematomas and a FVII coagulant activity (FVIIc) of less than 7% (Benlakal F et al. J Thromb Haemost 2011;9:1149). Little is known about prevention of bleeding in ‘minor surgical interventions’, important tools in modern medicine, bearing not a negligible risk of bleeding, as local hemostasis may not always be punctually achieved.

Aim:
Analysis of Replacement Therapy (RT) for minor surgeries in patients with FVII deficiency, prospectively reported in the Seven treatment Evaluation Registry (STER). Clinicaltrials.gov identifier: NCT01269138.

Methods:
Analysis of RTs used in 38 minor surgical procedures (34 patients; FVIIc:<1–20%). Minor surgical procedures were defined as suggested by Kitchens (Surgery and hemostasis. Textbook of Consultative Hemostasis and Thrombosis. 2007).

Results:
Reported interventions included: oral surgery (n=15), endoscopic biopsies (n=7), catheter insertions (n=3), ear-nose-throat and head-neck (n=5), mixed type (n=8). RT schedules were based on recombinant-activated FVII (rFVIIa; n=29), plasma-derived FVII (pdFVII; n=8), or Fresh-Frozen-Plasma (n=1). One-day RT schedule was employed in 27 procedures, 2–10 days in 11 procedures. Total doses ranged from 7.2–510 μg/kg (rFVIIa) and 9–300 IU/kg (pdFVII). FFP was given at a total dose of 50 ml/kg (1-day treatment, split into 4 doses of 12.5 ml). Antifibrinolytics were administered together with RT in 16 procedures (11 dental) for a minimum of 1 day to a maximum of 7 days. No bleeding nor thrombotic events occurred; one patient developed an inhibitor (Table 1).

Conclusion:
For most of the uncomplicated minor surgery procedures (single dental extractions, catheter insertions, endoscopic biopsies), one-day RT is sufficient with low to medium doses of rFVIIa (median 25 μg/Kg/bw) or pdFVII (median 18.5 UI/Kg/bw), possibly with more than one administration. In complicated and more elaborate interventions, longer-lasting RT schedules and higher doses may be needed.

Disclosures:
No relevant conflicts of interest to declare.
Genome-Wide shRNA Screen for DNA Damage Response Regulators in Human Hematopoietic Stem and Progenitor Cells
Authors: Gan Olga I , Milyavsky Michael , van Delft Mark F , Buzina Alla , Kalatskaya Irina , Ketela Troy , Stein Lincoln , Moffat Jason , Dick John E. 
Published: October 2019

Abstract
Abstract 1289
Hematopoietic stem cells due to their life-long function should protect genome integrity to avoid accumulation of genetic aberrations leading to malignant transformation or bone marrow failure. We reported recently that human HSC of cord blood origin are exquisitely sensitive to DNA damage-induced apoptosis. Thus, following 3Gy of ionizing radiation HSC show evidence of persistent DNA damage response and greater p53-dependent apoptosis in comparison with commited myeloid progenitors. To elucidate the molecular basis of these observations we carried out a genome-wide loss-of-function genetic screen using a library of 80 000 shRNA vectors targeting more than 16 000 human genes. A screen was performed on immortalized (by TLS-ERG infection) cord blood cells (TEX), which radio-sensitivity is similar to early hematopoietic cells. To find out the radio-protective hits we exposed infected cells to four rounds of 4Gy irradiation in three independent experiments. TEX cells exhibited steady increase of their proliferative potential after each irradiation exposure. Cells were gathered after each irradiation round and their DNA was subjected to sequencing to determine protective hits. Upon the analysis we recognized known regulators of DNA damage response (e.g. p53) and identified many genes that previously were not connected to genotoxic stress response. Thus, the knockdown of these genes was at least as effective as p53 knockdown in protection of TEX cells against gamma-irradiation. The validation of the chosen hits on TEX cells showed that about half of them indeed mediate the protection against irradiation. Further validation included real-time PCR of infected cells to ensure the absence of off-target effect along with Western blot analysis of affected protein. We followed up the investigation of chosen hits on primary human lineage-negative cord blood cells and observed that only few candidates were mediating the same effect on HSC/progenitors cells as on TEX cells. To further validate the effect of the most prominently effective hits we employed several shRNA vectors for the same target gene. Following this step of validation, we choose to investigate the knockdown of CHEK2, the gene with reported role in DNA damage response in several murine tissues. Our preliminary studies in long-term cytokine-supplemented cultures demonstrated that CHEK2 is involved in DNA damage response of human HSC and progenitors. The further investigation of the effect of CHEK2 knockdown on repopulating human HSC is currently underway. An integrated analysis of our observations revealed several putative CHEK2-centered molecular networks, which connect DNA damage response to HSC function.

Disclosures:
No relevant conflicts of interest to declare.
Characterization of Hematopoietic Stem Cell Function and Sensitivity in the Homologous Recombination Deficient Exonuclease1mut Mouse Model
Authors: Desai Amar , Qing Yulan , Gerson Stanton L. 
Published: October 2019

Abstract
Abstract 1293
Hematopoietic stem cell (HSC) maintenance is essential for sustained longevity and tissue function. The HSC population has lifelong self-renewing capabilities and gives rise to subsets of multipotent progenitor cells, and in turn a progeny of terminally differentiated mature cells consisting of all subtypes of the myeloid and lymphoid lineages. Long term reconstituting HSCs are necessary to replace these differentiated cells after losses caused by normal degradation or damage accumulation, with failure to replenish these stores being linked to a variety of human pathogeneses as well as aging phenotypes.
HSC populations require functional DNA repair pathways in order to maintain their reconstitution capabilities but little is known about the pathways involved or the mechanism of regulation. While the majority of HSCs are quiescent at steady state, endogenous or exogenous stress can force these cells into proliferation, and previous evidence has suggested that the HSC reliance on DNA repair changes with this mobilization. Quiescent HSCs are believed to depend on non-homologous end joining (NHEJ) for repair but prior literature has shown that once forced into cycle, the DNA repair dependency shifts and is shared between homologous recombination (HR) and NHEJ.
We use Exo1 deficiency as a model for homologous recombination loss in mice and demonstrate in vivo that HR is dispensable in quiescent HSCs. This is in contrast to loss of the complementary double strand break repair pathway NHEJ which has been shown to result in severe defects in HSC function. However when we force mobilize HSCs into cycle in vivo using the anti metabolite 5-fluorouracil we are able to demonstrate that the HR defects become detrimental to the animal as shown by increased cellular IR sensitivity and subsequent animal death. Additionally we use competitive repopulation studies to show that indeed the Exo1mut HSC population is more radiation sensitive after forced mobilization. This work begins to elucidate the consequences of the loss of homologous recombination in hematopoietic stem cells as well as the interplay between cell cycle status and DNA repair dependency.

Disclosures:
No relevant conflicts of interest to declare.
P/E Selectins and Their Ligand PSGL-1 Are Crucial for Macrophage-Mediated Multiple Myeloma Chemoresistance
Authors: Zheng Yuhuan , Yang Jing , Qian Jianfei , Hanabuchi Shino , Liu Zhiqiang , Lu Yong , He Jin , Li Haiyan , Shah Jatin J , Lan Yongsheng , Yi Qing 
Published: October 2019

Abstract
Abstract 130
Multiple myeloma (MM) bone marrow (BM) provides a homing microenvironment, which is important for tumor development, growth, proliferation, migration and chemoresistance. Our previous research has shown that macrophages (MΦ) are associated with malignant BM and confer MM cell chemoresistance in vitro. Based on these findings, we designed mechanistic studies to elucidate MΦ-mediated MM chemoresistance. MΦ protected MM cells from different chemotherapeutics, such as bortezomib, doxorubicin, dexamethasone, melphalan, or their combination-induced apoptosis. Cell-to-cell contact was crucial for such protection. Under a coculture condition, MΦ protected MM cells with wide ranging MM/MΦ ratio. Inhibition of phagocytosis did not affect the protection. An experiment examining MM patients' BM showed that MΦ was a dominant accessory cell population in patients' BM. Patients PBMC-derived MΦ or primary MΦ isolated from patient BM had protective activity. Further mechanistic study showed that surface molecules, such as P/E selectins (on MΦ) and their ligand PSGL-1 (on MM cells), were important for MΦ-mediated MM chemoresistance. Blockade antibodies against either P/E selectins or PSGL-1 significantly repressed MΦ-mediated drug resistance. MΦ had limited protection on PSGL-1-knocked down MM cells. Next, we examined intracellular signal transduction in MM cells, upon interaction with MΦs. Src family kinase and Erk1/2 kinase were activated in MM cells, after coculture with MΦs. Coculture also stimulated PSGL-1 and c-myc overexpression in MM cells. Inhibition of Src family kinase, Erk1/2 kinase, or c-myc by small molecule inhibitors impaired MΦ-mediated MM chemoresistance. The overexpression of PSGL-1, under coculture condition, could be repressed by IFN-α neutralization antibody. More importantly, coculture with MΦ could not stimulate Erk1/2 activation or c-myc overexpression in PSGL-1-knocked down MM cells, suggesting that Erk1/2 and c-myc were downstream of PSGL-1-initiated signal transduction. Finally, we established a NOD-SCID mouse model to test MΦ-mediated MM chemoresistance in vivo. MM tumors with MΦ infiltration grew significantly faster than MM, only, tumors and were more resistant to melphalan treatment. Overall, our data demonstrated a mechanism of MΦ-mediated chemoresistance, both in vitro and in vivo. Based on our findings, MΦ-targeted therapy in MM treatment may be beneficial to improve the effectiveness of MM chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.