bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Assessment of Surgical Thromboprophylaxis in a Tertiary Care Center
Authors: Robinson-Cohen Cassianne , Tagalakis Vicky , Dubois Marie-France , Pilon Danielle 
Published: April 2020

Abstract
Background. Venous thromboembolism (VTE) is a frequent surgical complication. The type of surgery and baseline patient VTE risk factors are important in defining postoperative VTE risk. The 2004 American College of Chest Physicians (ACCP) recommends implementation of pharmacologic thromboprophylaxis according to surgery type and VTE risk factors. We conducted a retrospective cohort study of surgical patients to determine adherence to the 2004 ACCP surgical thromboprophylaxis recommendations and to assess for predictors of non-adherence.
Methods. Using data from the administrative healthcare database CIRESSS (Centre Informatisé de Recherche Évaluative en Services en Soins de Santé), in patients admitted for surgery between January 1st and December 31st 2006 at the Centre Hospitalier Universitaire de Sherbrooke (CHUS), a tertiary care center in Sherbrooke, Quebec, Canada, we retrospectively assembled a cohort of all consecutively admitted surgical patients who met ACCP criteria for pharmacologic thromboprophylaxis. We assessed the proportion of patients who received in the 24 hours pre- and post-surgery a prescription for thromboprophylaxis. We used conditional logistic regression to determine clinical characteristics associated with an absent prescription. The incidence of objectively-defined symptomatic postoperative VTE was assessed at three months.
Results. Of 2286 surgical admissions that met ACCP recommendations for pharmacologic thromboprophylaxis, 1852 (81%) received thromboprophylaxis and 434 (19%) did not. Male sex (odds ratio (OR): 1.9, 95% confidence interval (CI) (1.4–2.4)), age &lt;40 years (OR: 1.8, 95% CI (1.2–2.9)), absent varicose veins (OR: 3.2, 95% CI (1.1–10.0)), pregnancy within 3 months of surgery (OR: 8.5, 95% CI (3.5–20.8)), a moderate risk for post-operative VTE as per ACCP criteria (OR: 4.4, 95% CI (2.9–6.52)), non-major surgery (OR: 4.5, 95% CI (2.3–8.8)), short-duration hospitalization (2–3 days vs. 13 days or more) (OR: 15.3, 95% CI (9.6–24.4)), absence of active cancer (OR: 1.6, 95% CI (1.2–2.1)), absence of heart failure (OR: 1.8, 95% CI (1.1–2.8)), and non-orthopaedic surgery (OR: 28.2, 95% CI (15.9–49.9)) were associated with lack of pharmacologic thromboprophylaxis. At three months following surgery, 16 patients (0.7%) developed VTE, and the adjusted relative risk of VTE in patients without thromboprophylaxis was 2.1 (95% CI:0.5–7.9).
Conclusions. Though surgical thromboprophylaxis was observed in 81% of surgical patients, 19% of patients who met criteria for ACCP thromboprophylaxis did not receive prophylaxis. Targeted recommendations in particular toward pregnant women undergoing non-obstetrical surgery, patients with short duration hospitalization, and patients undergoing non-orthopaedic surgery may ameliorate thromboprophylaxis compliance rates, which in turn may impact on post-operative VTE risk.
Anticoagulant Effects of the Low-Molecular-Weight Heparin Certoparin in Combination with Phenprocoumon in Patients with Recent Atrial Fibrillation Undergoing Cardioversion
Authors: Harenberg Job , Wierdack Jolanta , Weiss Christel , Giese Christina , Abletshauser Claudia , Tebbe Ulrich 
Published: April 2020

Abstract
Patients with recent onset of atrial fibrillation (AF) receive anticoagulation with low-molecular-weight heparin (LMWH) and coumarin targeted at an INR of 2 to 3. Recently, LMWH is given alone before cardioversion followed by coumarin. At present, no method is available to determine the combined effect of LMWH and coumarin in order to get information on the in vivo anticoagulant status of these patients. Patients with recent onset of AF (n=200) received 8.000 IU LMWH certoparin bid upon entry into the study. Phenprocoumon was started after electrical cardioversion. LMWH was stopped after 2 days within therapeutic INR range of phenprocoumon. The clincial data have been published (Clin Res Cardiol 2008). Blood samples were drawn from patients before LMWH administration (visit 1, V1), before start of phenprocoumon (V4) and after reaching the desired INR range and before stopping LMWH (V5) to determine a set of anticoagulant parameters. The study was accepted by the local ethics committees and patients gave written informed consent. Activated partial thromboplastin time, chromogenic factor Xa assay, heptest time values, prothrombinase-induced clotting time and tissue factor pathway inhibitor demonstrated the anticoagulant effect of certoparin at V4 and V5. Results of these parameters differed between V1 and V4 as well as between V1 and V5 (all p&lt;0.001) but not between V4 and V5. Prothrombin time was prolonged at V5 versus V1 and V4 (both p&lt;0.001). D-Dimer and prothrombinfragment F1+2 significantly decreased from V1 to V4 and from V4 to V5 (all p&lt;0.001). Endogenous thrombin potential assay (ETP) was inhibited stronger at V4 compared to V1, and at V5 compared to V4 (both p&lt;0.001). D-Dimer, F1+2 and ETP are the parameters reflecting the combined anticoagulant effect of certoparin and phenprocoumon while overlapping anticoagulation with these compounds in patients with recent AF for electrical cardioversion. The clinical effects on thromboembolic or bleeding incidences remain to be determined.
Favorable Immunologic Response Profile to Recombinant Thrombin Application in Surgery: An Integrated Analysis of 8 Clinical Trials
Authors: Chapman William , Renkens Kenneth , Gamelli Richard , Randleman Carlton , Ballard Jeffrey , Alexander W. Allan 
Published: April 2020

Abstract
Recombinant thrombin (rThrombin) is an active topical hemostat approved by the FDA as an aid to hemostasis. Treatment with thrombin derived from bovine sources has occasionally been associated with adverse events which appear to be related to the formation of antibodies against bovine thrombin and/or Factor V. The safety and immunogenicity of rThrombin have been evaluated in 8 clinical trials: 1 Phase 1 study, 5 Phase 2 studies, 1 randomized, double-blind Phase 3 study, and 1 open-label, single-group Phase 3b study. Pooled results from these trials provide a consistent and clinically relevant summary of safety information on the use of rThrombin in surgery. These trials utilized standardized data collection methods; more than 100 investigators from over 60 institutions participated. With 514 subjects treated with rThrombin in clinical trials to date (cut-off date July 2008), these results represent the largest safety database available for any commercially-available thrombin product. Standard safety measures were collected prior to surgery (baseline) through Day 29 post-surgery. Immunogenicity was evaluated at baseline and Day 29 using enzyme-linked immunosorbent assays and a time-to-clot assay to measure neutralizing potential of any detected anti-rThrombin antibodies. Of the subjects for whom data are currently available (N=514), 54% were male and 46% were female. Mean age was 57.0 years (SD, 15.7; range, 12–89 years). The following surgery types were represented: spine, 32% of patients; liver, 14%; peripheral arterial bypass, 23%; arteriovenous graft, 18%; burn, 12%. The median dose of rThrombin was 10,000 IU (range, 1000–50,000 IU). Topical application of rThrombin was well tolerated by study subjects. Common adverse events (AEs; reported by ≥10% of subjects) were similar regardless of surgery type and were consistent with the post-surgical setting. Common AEs included incision site complication, procedural pain, nausea, constipation, pyrexia, anemia, vomiting, insomnia, incision site pain, and pruritus. No single serious adverse event type occurred in &gt;1% of patients. Twelve of 514 subjects (2.3%) had anti-rThrombin product antibodies at baseline, a finding that is consistent with reports of antibodies to other recombinant forms of endogenous proteins. None of the 12 subjects with anti-rThrombin product antibodies at baseline had a change in titer ≥1.0 unit at Day 29. Among subjects who did not have anti-rThrombin product antibodies at baseline, 5/502 (1.0%) had detectable antibodies at Day 29. In total, 5/514 subjects (1.0%) were antibody positive at Day 29. None of the antibodies neutralized native human thrombin. These clinical studies, enrolling 514 subjects to date, collectively demonstrate that rThrombin is well-tolerated and has a favorable immunologic response profile when used in numerous surgical settings.
The Overall Haemostatic Potential (OHP) Assay Detects Abnormalities in Fibrinolytic Factors
Authors: Curnow Jennifer L , Morel-Kopp Marie-Christine , Ward Christopher 
Published: April 2020

Abstract
No routine assays are available which quantify abnormalities in the fibrinolytic system. The Overall Haemostatic Potential (OHP) assay is a global assay of fibrin generation and fibrinolysis. Our aim in this study was to assess changes in fibrinolysis measured by the OHP assay in samples with variable levels of the different components of the fibrinolytic system: plasminogen, a2-antiplasmin, PAI-1 and TAFI. Plasmas deficient in these factors were obtained commercially. Samples were spiked with Lys-plasminogen, Glu-plasminogen, PAI-1, TAFI or pooled normal plasma to produce serial increases in these factors. Potato tuberose carboxypeptidase inhibitor (PTCI) was also used to inhibit TAFI in PNP and patient samples. OHP assays were performed utilizing either thrombin (0.03 IU/ml) or tissue factor (5 pM) to trigger fibrin generation, and rt-PA (350 ng/ml) to trigger fibrinolysis. Data analysis involved calculation of Spearman correlations for OHP assay parameters and concentrations of the various fibrinolytic factors tested. The OHP assay demonstrated markedly reduced fibrinolysis in plasminogen deficient plasmas, which normalised when plasminogen levels were increased to the normal range. At elevated Lys-plasminogen levels fibrin generation was impaired. Overall fibrinolytic potential was mildly increased in a2-antiplasmin deficiency. PAI-1 depleted plasma had mildly increased fibrinolysis compared with PNP but with addition of PAI-1, to concentrations of 300 ng/ml or higher, fibrinolysis was markedly impaired. TAFI deficient plasma had reduced fibrin generation but no change in fibrinolysis was seen in spiked samples, even with elevated TAFI levels. Representative hypofibrinolytic patient samples showed normalisation of fibrinolysis with TAFI inhibition by PTCI.
The OHP assay shows appropriate changes in OFP with variations in the concentrations of activators and inhibitors of the fibrinolytic system. The assay provides a simple means of quantifying overall fibrinolysis and is sensitive to abnormalities in individual components of the fibrinolytic system. It should be useful for investigating fibrinolytic abnormalities in patients, where no routine assay is currently available.
Biological Activity of the First Epidermal Growth Factor-Like Domain of Rat Coagulation Factor VII
Authors: Mei Heng , Hu Yu , Wang Huafang , Zhang Xiaoping , Guo Tao , Huang Shiang 
Published: April 2020

Abstract
Abstract: The first epidermal growth factor-like (EGF1) domain of coagulation factorVII (FVII) is essential for binding with tissue factor (TF) in human. We hypothesized that the function of rat FVII (rFVII) EGF1 domain might be the same as the human being’s. The clone and expression of rFVII EGF1 domain would be helpful in studying the anticoagulant drugs based on FVII/TF interaction. Accordingly, the model of rat TF expression in vitro was established by lipopolysaccharide(LPS) induction. We amplified the EGF1 domain from a rat liver by reverse transcriptase PCR (RT-PCR), and then a fusion expression vector named pET28a-EGFP-EGF1 was constructed. After expression in Ecoli BL21 cells, the EGFP-EGF1 fusion proteins were analyzed for binding affinity to rat TF by confocal microscope and flow cytometry. Prothrombin time assay was employed to test biological activity of the fusion protein by using FVII depleted human plasma. The resulting plasmid expressed fusion protein EGFP-EGF1 in the soluble form in E.coli BL21, and the recombinant protein was purified successfully with a major band at 36KD in SDS-PAGE(Figure 1). The purified EGFP-EGF1 fusion proteins could definitely depress recombinant mouse FVII((rmFVII) binding with rat TF(rTF)(70.06%VS 53.80%, P&lt; 0.01)(Figure 2 &3). However, the proteins lost the activity of coagulation when compared to that of blood serum of normal SD rats (56.8sVS 17.8s, P&lt; 0.01). (Table 1)We conclude that the rat EGF1 region could specifically bind to TF without the ability of coagulation, and it might facilitate the development of molecular target study in anti-thrombosis treatment.
Table 1. Prothrombin Time test of Fusion proteins
Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Figure 4 Figure 4.
Combined Coagulation Factor XI and Factor XII Deficiency in An Asymptomatic Female
Authors: Herrada Juan , Adcock Dorothy M , Casillas Arturo , Jobe Jeff T. , Noble Luis S. , Landeros Mark M. 
Published: April 2020

Abstract
Background: Multiple combined coagulation factor deficiencies have been reported, although the genetic defects associated with these conditions remain largely unknown. We present an asymptomatic female with a persistent deficiency of both coagulation Factor XI (FXI) and Factor XII (FXII). To our knowledge, this particular combination of coagulation factor deficiency has not been previously reported.
Case Report: In February 2004 a healthy 33 year-old white female without personal or family medical history presented with an elevated partial thromboplastin time (PTT) incidentally found during a routine pre-operative evaluation. Her prothrombin time (PT) was normal. Her PTT was 45 seconds (reference interval 23–37 seconds), and normalized with 1:1 mixing studies of patient and normal plasma. Preliminary laboratory evaluation included negative tests for the presence of a Lupus Anticoagulant, a normal serum albumin level, and a normal urinalysis. Additional laboratory testing of coagulation and included FXI and XII activities, measured by means of a one stage APTT-based clotting assay using APTT reagent (Automated APTT, Trinity Biotech, Bray Ireland), congenitally depleted deficient plasma (HRF, Inc, Raleigh NC) using the MDA II Trinity Biotech, Bray Ireland). FXI was 46% (reference range 60–150) and FXII was 42% (reference range 50–150). In March 2004, a repeated the laboratory evaluation showed a FXI of 41% and a FXII of 46%. In April 2006, FXI was 49%, and FXII was 40%. Is to be noted that the patient has never had a documented thromboembolic episode or excessive bleeding, despite the exposure, respectively, to estrogen supplementation for seven years, to a full-term pregnancy, and to an abdominal surgical event.
Conclusion: Although modern laboratory methods are able to identify novel combinations of coagulation defects, their clinical significance requires additional investigation.
Nramp1 Promotes Efficient Macrophage Recycling of Iron Following Phenylhydrazine-Induced Hemolytic Anemia
Authors: Soe-Lin Shan , Andriopoulos Bill , Andrews Marc , Schranzhofer Matthias , Kahawita Tanya , Santos Daniel Garcia , Azad Nabila , Apte Sameer Sadashiv , Ponka Prem 
Published: April 2020

Abstract
Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells such as macrophages and neutrophils. Based on our earlier in vitro study (Soe-Lin et al. Exp Hematol.2008;36:929–937), we hypothesize that Nramp1 may participate in the recycling of iron acquired through the phagocytosis of senescent red blood cells by macrophages. In order to examine the effect of Nramp1 on iron recycling in vivo, the iron parameters of wildtype (Nramp1+/+) and Nramp1 knockout mice (Nramp1−/−) were analyzed following both acute and chronic induction of hemolytic anemia by phenylhydrazine treatment. We observe that untreated Nramp1−/− mice exhibited greater serum transferrin saturation and splenic iron content, higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression, and dramatically lower hepcidin mRNA levels than untreated Nramp1+/+ mice. Significant iron loading of the reticuloendothelial organs was found to increase with age in knockout mice. Following acute treatment with the hemolytic agent phenylhydrazine, Nramp1−/− mice experienced a significant decrease in serum iron levels and hematocrit, while their Nramp1+/+ counterparts were relatively unaffected. Following a month-long phenylhydrazine regimen, Nramp1−/− mice retained markedly increased quantities of iron within the liver and spleen, and exhibited greater splenomegaly and reticulocytosis than wild-type mice. Furthermore, while hepcidin mRNA levels decreased following chronic phenylhydrazine treatment in both Nramp1+/+ and Nramp1−/− mice, this effect was significantly more pronounced in Nramp1−/− mice. The data presented in this report suggest that in the absence of Nramp1, iron accumulates to a greater degree within reticuloendothelial organs such as the liver and spleen following acute and chronic hemolytic anemia. We hypothesize that the low hepcidin mRNA levels seen in Nramp1−/− mice are a response to a diminished availability of iron for erythropoiesis resulting from the aberrant increase in iron retention within their splenic reticuloendothelial macrophages. Our observation of increased DMT1 and ferroportin within the duodenums of the Nramp1−/− animals imply that the increase in transferrin saturation despite the impaired iron release from erythrophagocytosing macrophages occurs due to a compensatory increase in iron absorption from the diet. These findings are consistent with our hypothesis that Nramp1 promotes the efficient recycling of iron in erythrophagocytosing macrophages.
The Use of Tetradenoylphorbol Acetate Stimulated Peripheral Blood Cells for Interphase Fluorescence In-Situ Hybridization Analysis May Enhance Its Prognostic Value for Patients with Chronic Lymphocytic Leukemia
Authors: Delgado Julio , Aventin Anna , Briones Javier , Sanchez Jana , Nomdedeu Josep , Sierra Jorge 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) is a mature B-cell malignancy characterized by a variable clinical course. Genomic aberrations, as identified by interphase fluorescent in situ hybridization (I-FISH), have a remarkable predictive power in terms of response to therapy, time to first treatment and overall survival of these patients. I-FISH studies can be performed either on unstimulated peripheral blood mononuclear cells (I-FISH-PBMC) or on tetradecanoylphorbol acetate (TPA) stimulated peripheral blood cells (I-FISH-TPA). We have previously observed that I-FISH-TPA could identify genomic abnormaties that might be overlooked with I-FISH-PBMC.
The aim of the study was to evaluate whether this increased detection of genomic abnormalities, as identified by I-FISH-TPA, was clinically relevant for a group of consecutive CLL patients.
Blood samples from 47 CLL patients were stimulated with TPA and cultured in RPMI medium supplemented with fetal calf serum. Peripheral blood mononuclear cells were isolated using density-gradient centrifugation and fixed according to standard methods. I-FISH was performed on both TPA stimulated and unstimulated cells using 11q22.3 (ATM), 13q14 (13S272), 17p13.1 (p53), and centromeric 12 (D12Z3) probes. 200 nuclei were evaluated for each probe, and cut-off points were set at 6%, 7%, 5% and 2% for del(11q), del(13q), del(17p) and trisomy 12, respectively. Metaphase FISH and conventional cytogenetics were also performed in selected cases. For all patients, chemotherapy was initiated according to Cheson criteria and treatment-free and overall survival curves were plotted using SPSS software.
Following a modified version of Dohner’s hierarchical model, patients were divided in those with del(17p) and/or del(11q) and those with other or no genomic abnormalities. Fourteen cases with negative or bordeline results with I-FISH-PBMC became positive with I-FISH-TPA for del(11q) (2 cases), del(13q) (9 cases) and trisomy 12 (3 cases). In all but one patient, either conventional karyotyping or metaphase FISH confirmed these abnormalities. I-FISH-TPA provided a better prediction of treatment-free interval compared to I-FISH-PBMC (P= 0.002 vs 0.019, see Figures 1 and 2). In particular, two patients with no cytogenetic abnormalities detected by I-FISH-PBMC required chemotherapy 3 and 11 months after diagnosis, more in keeping with the presence of del(11q) found using I-FISHTPA. Furthermore, I-FISH-TPA also improved the overall survival prediction compared to I-FISH-PBMC (P= 0.036 vs 0.042).
In summary, I-FISH-TPA increased the detection rate and had an improved prognostic value compared to I-FISH-PBMC. Further studies with larger numbers of patients are warranted.
Figure Figure Figure Figure
PKCβ Is Essential for the Development of CLL in the TCL1 Transgenic Mouse Model: Validation of PKCβ as a Therapeutic Target in CLL
Authors: Egle Alexander , Holler Claudia , Pinon Josefina D. , Denk Ursula , Heyder Christoph , Greil Richard 
Published: April 2020

Abstract
The development and the propagation of chronic lymphocytic leukemia (CLL) has been linked to signalling via the B-cell receptor (BCR). Protein kinase C (PKC) beta is an essential signalling element of the BCR and was recently shown to be overexpressed in human CLL. We used the TCL1 transgenic mouse model to directly target PKC beta in the development of murine CLL. While loss of PKC beta in wild type mice leads to a complete loss of CD5+ B cells in these mice, the targeted disruption of the PKC beta gene in Tcl1 transgenic mice did not abrogate the accumulation of CD5 positive B cells in the pretumor phase in these mice. This suggests that the basic survival signal transmitted by PKC beta in B1 cells can be substituted by the augmented Akt signalling in the Tcl1 transgenic cells. Yet despite this, PKC beta deficient TCL1 transgenic mice did not develop a CLL disease, suggesting a role of PKC beta in the establishment of the malignant clone. In fact PKC beta is likely to be essential for transformation in limiting the BCR signal via a negative feedback loop, suggesting that BCR signalling strength is an important component of the transformation process. In order to provide support for the potential of PKC beta as a drug target in CLL we targeted PKC beta with the specific inhibitor Enzastaurin. This led to killing of human CLL samples in vitro and this was independent of risk factors in the samples analysed. We thus propose that PKC beta may be a relevant target for the treatment of CLL.