bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels
Authors: Seemungal Terence , MacCallum Peter , Paul Elizabeth , Donaldson Gavin , Bhowmik Angshu , Jeffries Donald , Meade Thomas , Wedzicha Jadwiga 
Published: March 2018

SummaryRespiratory tract infections may acutely increase risk from coronary heart disease (CHD), though the mechanisms have not been defined. Patients with chronic obstructive pulmonary disease (COPD) are prone to repeated exacerbations that are often associated with respiratory infections. These patients also have increased cardiovascular morbidity and mortality. We hypothesized that transient acute increases in plasma fibrinogen, an independent risk factor for CHD, could occur at COPD exacerbation (mediated through a rise in IL6) and thereby provide a mechanism linking respiratory infection to risk of coronary heart disease.93 COPD patients [mean (SD) age 66.8 (8.1) years] were followed regularly over one year, with daily diary card monitoring of respiratory symptoms and peak expiratory flow rate (PEFR); 67 patients [mean FEV1 1.06 (0.44) l, FVC 2.43 (0.79) l] were seen during 120 exacerbations. At each visit spirometry was measured and blood samples taken for plasma fibrinogen and Interleukin-6 (IL-6) levels.At baseline, the mean (SD) plasma fibrinogen was elevated at 3.9 (0.67) g/l in the 67 patients with exacerbations during the study and the median (IQR) IL-6 at 4.3 (2.4 to 6.8) pg/ml. Plasma fibrinogen increased by 0.36 (0.74) g/l at exacerbation (p <0.001), with IL-6 levels rising by 1.10 (−2.73 to 6.95) pg/ml (p = 0.008). There was a relation between the changes in fibrinogen at exacerbation and IL-6 levels (r = 0.348, p <0.001). Multiple regression revealed significantly greater rises in fibrinogen when exacerbations were associated with purulent sputum (b = 0.34 g/l; p = 0.03), increased cough (b = 0.31 g/l, p = 0.019) and symptomatic colds (b = 0.228; p = 0.024).Plasma fibrinogen levels were elevated in stable patients with COPD and may contribute to the increased cardiovascular morbidity and mortality in these patients. COPD exacerbations increased serum IL-6 levels, leading to a rise in plasma fibrinogen. Thus acute rather than chronic infection may have a role in predisposing to coronary heart disease or stroke.
Fluid Shear Stress Increases the Intra-cellular Storage Pool of Tissue-type Plasminogen Activator in Intact Human Conduit Vessels
Authors: Sjögren Lena , Gan Liming , Doroudi Roya , Jern Christina , Jungersten Lennart , Jern Sverker 
Published: March 2018

SummaryWe investigated the effect of shear stress on the expression of tissuetype plasminogen activator (t-PA) in intact human conduit vessels. Human umbilical veins were exposed to high or low shear stress (25 vs < 4 dyn/cm2) at identical intraluminal pressure (20 mmHg) for 1.5, 3, and 6 h in a new computerized biomechanical perfusion system. High shear perfusion induced a marked, time-dependent increase in t-PA immunostaining in both the endothelium and the media. t-PA relative to GAPDH gene expression increased by 54 ± 14% in highcompared to low-sheared vessels (p = 0.002). By contrast, t-PA release into the perfusion medium was similar in vessels perfused under high or low shear stress conditions. The results show that shear stress independently of pressure is a potent fluid mechanical stimulus for upregulation of the intracellular storage pool of t-PA in the vascular wall of fresh human conduit vessels. The shear effect is associated with an increased t-PA gene expression.
Assay of Functional Plasminogen in Rat Plasma Applicable to Experimental Studies of Thrombolysis
Authors: Bangert Kristian , Thorsen Sixtus 
Published: March 2018

SummaryAn improved sensitive, specific, precise and accurate assay of plasminogen in rat plasma was developed. It is performed in 96-well microtiter plates and can be completed within one hour. The assay is based on activation of plasminogen by human urokinase-type plasminogen activator (uPA) and simultaneous measurement of generated plasmin with the specific plasmin substrate H-D-Val-Phe-Lys-4-nitroanilide (S-2390), using purified native rat plasminogen for calibration. The concentration of S-2390 in the final reaction mixture during the whole reaction period is much greater than the K
m value (≈20 µM) for rat plasmin-cleavage of S-2390 ensuring that hydrolysis of substrate follows zero order kinetics and that the substrate produces a 20-35 fold decrease in rate of inhibition of plasmin by its target inhibitors in plasma. Analogous to the human system the target plasma inhibitors of rat plasmin are shown to be plasmin inhibitor and α-macroglobulins. Tranexamic acid (0.8 mM) is incorporated in the reaction mixture resulting in a 19-fold increase in the rate of plasminogen activation and presumably an about 50-fold decrease in the rate of inhibition of generated plasmin by plasmin inhibitor. The assay is suitable for accurate measurement of plasminogen in samples obtained from animals containing pharmacological concentrations of uPA or tissue-type plasminogen activator (tPA) in their plasma when in vitro plasminogen activation is blocked at pH 5 by collecting blood in acidic anticoagulant. Judged from in vitro experiments formation of catalytic active plasmin-α-macroglobulin complexes during massive activation of plasminogen in vivo does not interfere with the assay.
Pre-Clinical Pharmacological Profile of the Novel Glycoconjugate Org 36764 with both Factor Xa and Thrombin (IIa) Inhibitory Activities
Authors: van Amsterdam Ronald , van Dinther Theo , Tromp Marijke , Meuleman Dirk , Vogel Gerard 
Published: March 2018

SummaryOrg 36764, is an antithrombin III (AT) and thrombin binding carbohydrate, which accelerates the inactivation of both factor Xa and thrombin by AT. It displays in buffer an anti-Xa and anti-thrombin activity of 415 and 2 U/mg, respectively, compared to 172 and 114 U/mg, respectively, for unfractionated heparin (UFH). Org 36764 does not cross-react with HIT (heparin induced thrombocytopenia) antibodies and is not neutralised by PF4. In experimental models in rats, on a molar basis, Org 36764 was more active than the pentasaccharide SanOrg 34006 (= AT binding domain of Org 36764) in arterial thrombosis, but both were equally active in venous thrombosis. In arterial thrombosis following endothelial damage by ferric chloride, Org 36764 was more active than the LMW heparin enoxaparin and SanOrg 34006 and similar active to UFH. At AT saturating doses the bleeding enhancement was not more than 3.5 times the control value. Org 36764 was more active in suppressing in vivo thrombus formation on stents than UFH, SanOrg 34006 or a combination of ticlopidine and aspirin. The results indicate that the novel drug Org 36764 is a drug with antithrombotic potential against venous and arterial thrombosis.
Verotoxin-1 Induces Tissue Factor Expression in Human Umbilical Vein Endothelial Cells through Activation of NF-κB/Rel and AP-1
Authors: Takada Kimihiko , Higuchi Toshiyuki , Sugiyama Junichi , Ishii Hidemi 
Published: March 2018

SummaryThis study examined the effect of verotoxin-1 (VT-1), which is released from Escherichia coli O157:H7, on endothelial expression of tissue factor (TF), a cofactor required to initiate blood coagulation. In order to elucidate the molecular basis for development of hemolytic uremic syndrome (HUS) in patients infected with E. coli O157:H7, human umbilical vein endothelial cells (HUVECs) were exposed to purified VT-1. VT-1 increased both TF activity and TF mRNA in HUVECs without loss of cell viability in a time-and dose-dependent manner from 0.1 to 10 ng/ml VT-1. Nuclear proteins extracted from VT-1-stimulated HUVECs bound to the consensus NF-κB/Rel and AP-1 binding oligonucleotides in a dose-dependent manner within 2 h after the stimulation in electrophoretic mobility shift assays (EMSA). Nuclear proteins from VT-1-stimulated HUVECs formed two complexes with the NF-κB/Rel binding motif in the human TF promoter (TF-κB motif). The supershift assays, using antibodies for human p65, p50 or c-Rel, indicated that the lower complex was composed of p65/p50 and the higher complex was a p65 homo-or hetero-dimer with the Rel family, except c-Rel. The human TF promoter contains two AP-1 binding sites, the proximal and distal AP-1 binding sites. The supershift assays indicated that AP-1 containing mainly c-Jun and JunD, positively bound to the proximal AP-1 motif of TF (TF-AP-1). The distal TF-AP-1 motif did not show positive binding with nuclear proteins from VT-1-stimulated HUVECs. Pretreatment of HUVECs with curcumin, an inhibitor of NF-κB/Rel activation, synthesis of c-Jun mRNA and binding of activated AP-1 with AP-binding oligonucleotide, prevented the VT-1 induced increase in TF mRNA and activity in VT-1-stimulated HUVECs. Curcumin also inhibited NF-κB and AP-1 binding to TF-κB and proximal TF-AP-1 oligonucleotides, respectively, in a dose-dependent manner. The present work suggests that both the NF-κB/Rel and AP-1 activated in endothelial cells by stimulation with VT-1 binds to the TF-κB and proximal AP-1 binding sites, respectively, of the TF promoter.
Heparin-induced Thrombocytopenia: Towards Consensus
Authors: Warkentin Theodore , Chong Beng , Greinacher Andreas 
Published: March 2018

SummaryHeparin-induced thrombocytopenia (HIT) is a drug-induced, immunoglobulin-mediated thrombocytopenic disorder that is important for at least three reasons. First, it is a relatively common drug-induced immunohematologic adverse reaction. Second, it is frequently complicated by life- and limb-threatening thrombotic complications. And third, there remains uncertainty about the optimal treatment approach for these patients. Recently, there has emerged increasing consensus on such important issues as the frequency, pathogenesis, and diagnostic testing, which we will summarize here. Further, a greater appreciation of the activation of the coagulation pathways in this syndrome indicate a rationale to treatment approaches that emphasize thrombin inhibition (eg. danaparoid sodium; hirudin and its analogues).
Factor V Q506 Mutation (Activated Protein C Resistance) Associated with Reduced Intrapartum Blood Loss – a Possible Evolutionary Selection Mechanism
Authors: Svensson Peter , Dahlbäck Björn , Maršál Karel , Lindqvist Pelle 
Published: March 2018

Summary
Objectives. To ascertain whether relationship exists between the presence of APC resistance [a hypercoagulable state due to a mutation (R506Q) in the factor V gene] and the occurrence of pre-eclampsia (PE), intrauterine growth retardation (IUGR), and pregnancy bleeding complications. Design. A retrospective study. Subjects. A study group of 122 women with PE and/or IUGR during a recent pregnancy and a control group of 465 healthy pregnant women. Results. A significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup as compared to the non-APC-resistant subgroup was suggested by reduced intrapartum blood loss, and pre- and postpartum haemoglobin measurements. The prevalence of APC resistance in the PE and IUGR subgroups did not differ significantly from that in the control group. Conclusion. The remarkably high prevalence of the potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding on carriers of the FV:Q506 allele.
Factor XII Determinations in the Presence and Absence of Phospholipid Antibodies
Authors: Jones D. W. , Winter M. , Gallimore M. J. 
Published: March 2018

SummaryFactor XII (FXII) levels were determined in plasma samples from 29 normal donors, 10 patients with inherited FXII deficiency (all lupus anticoagulant [LA] negative) and 67 LA positive patients, using clotting (FXIIct), chromogenic substrate (FXIIcs) and immunochemical (FXIIag) assays. Excellent correlations were obtained in the three FXII assays with the LA negative samples and between the FXIIcs and FXIIag assays in the LA positive samples. Correlations between both the FXIIcs and FXIIag with FXIIct in the LA positive patients were poor. Of 67 LA positive samples studied, 25 (37.3%) showed lower values in the FXIIct assay; 13 (19.4%) of these patients were pseudo FXII deficient with values of FXII below the lower limit of normal.These results indicate that a diagnosis of FXII deficiency can be made inappropriately in the presence of phospholipid antibodies and that such a diagnosis should not be made by FXIIct assay alone.
Rapid Detection of D-dimer Using a Fiber Optic Biosensor
Authors: Rowe Chris , Bolitho Jeni , Jane Andrew , Bundesen Peter , Rylatt Dennis , Eisenberg Paul , Ligler Frances 
Published: March 2018

SummaryWe describe a rapid and sensitive method for detection and quantification of D-dimer and other crosslinked fibrin degradation products (XL-FDPs), which are present in elevated concentrations in patients with sepsis and thrombotic disorders. The method utilizes a sandwich fluoroimmunoassay immobilized in the sensing region of an evanescent wave biosensor. Physiological concentrations of D-dimer and high molecular weight XL-FDP could be determined in buffer and plasma samples on calibrated fibers in 11 min. Samples from septic patients were assayed using ELISA and the fiber optic method; concentrations determined by fiber optic assay were strongly correlated with those determined by ELISA (r = 0.918); intra- and inter-assay errors were comparable to those from ELISAs. Given its accuracy and rapid response time, this fiber optic biosensor shows great potential for development as a diagnostic tool.
Platelet Activation and Aggregation Induced by Recombinant von Willebrand Factors Reproducing Four Type 2B von Willebrand Disease Missense Mutations
Authors: Hilbert Lysiane , Mazurier Claudine , de Romeuf Christophe 
Published: March 2018

SummaryType 2B of von Willebrand disease (vWD) refers to qualitative variants with increased affinity of von Willebrand factor (vWF) for platelet glycoprotein Ib (GPIb). All the mutations responsible for type 2B vWD have been located in the A1 domain of vWF. In this study, various recombinant von Willebrand factors (rvWF) reproducing four type 2B vWD missense mutations were compared to wild-type rvWF (WT-rvWF) for their spontaneous binding to platelets and their capacity to induce platelet activation and aggregation. Our data show that the multimeric pattern of each mutated rvWF is similar to that of WT-rvWF but the extent of spontaneous binding and the capacity to induce platelet activation and aggregation are more important for the R543Q and V553M mutations than for the L697V and A698V mutations. Both the binding of mutated rvWFs to platelets and platelet aggregation induced by type 2B rvWFs are inhibited by monoclonal anti-GPIb and anti-vWF antibodies, inhibitors of vWF binding to platelets in the presence of ristocetin, as well as by aurin tricarboxylic acid. On the other hand, EDTA and a monoclonal antibody directed against GPIIb/IIIa only inhibit platelet aggregation. Furthermore, the incubation of type 2B rvWFs with platelets, under stirring conditions, results in the decrease in high molecular weight vWF multimers in solution, the extent of which appears correlated with that of plasma vWF from type 2B vWD patients harboring the corresponding missense mutation. This study supports that the binding of different mutated type 2B vWFs onto platelet GPIb induces various degrees of platelet activation and aggregation and thus suggests that the phenotypic heterogeneity of type 2B vWD may be related to the nature and/or location of the causative point mutation.
Outpatient Use of Low Molecular Weight Heparin (Dalteparin) for the Treatment of Deep Vein Thrombosis of the Upper Extremity
Authors: Savage K. J. , Wells P. S. , Schulz V. , Goudie D. , Morrow B. , Cruickshank M. , Kovacs M. J. 
Published: March 2018

SummaryUpper extremity deep vein thrombosis (DVT) is now recognized as a major cause of morbidity and mortality. There is little information regarding the most effective treatment of this condition. We report a prospective cohort study of the use of low molecular weight heparin (LMWH) in the outpatient management of upper extremity DVT. Forty-six patients were managed as outpatients for objectively documented upper extremity DVT with dalteparin (200 aXa u/kg), for a minimum of five days. Warfarin was usually initiated on the first day with a target INR of 2.0-3.0. Most patients had an underlying malignancy or a history of a central line. All patients were followed for 12 weeks from diagnosis. Only one patient had a major bleed. No patients developed pulmonary emboli. One patient had a recurrence of DVT during the treatment with LMWH with extension of the existing thrombus. Seven patients died, all due to their underlying disease. This study supports the safety and effectiveness of dalteparin in the treatment of upper extremity DVT. Given that these patients were treated as outpatients, there is a potential for huge cost savings.
The Levels of Factor XIIa Generated in Human Plasma on an Electronegative Surface Are Insensitive to Wide Variation in the Concentration of FXII, Prekallikrein, High Molecular Weight Kininogen or FXI
Authors: Mitropoulos K. A. 
Published: March 2018

SummaryThe contribution of the various components of the contact system in the generation of factor XIIa (FXIIa) and of kallikrein (KRN) on an electronegative surface and the release of the generated enzymes to the bulk phase was examined in mixtures of normal human plasma and plasmas congenitally deficient in these components. The incubation of normal human plasma in the presence of sulphatide vesicles (40 μM) resulted in a fast generation of amidolytic activities due to FXIIa and to KRN followed by slower first-order inactivation rates of FXIIa (k’FXIIa) and of KRN (k’KRN) due to the presence of esterase inhibitors. Variation of the levels of factor XII (FXII), over a wide range, showed little effect on levels of FXIIa and of KRN but no activities were detected in 100% FXII-deficient plasma. The variation of prekallikrein (PKRN) concentration showed little effect on the generation of FXIIa but the generation of KRN declined linearly with the decrease in the level of PKRN. No activities were detected on treatment of PKRN-deficient plasma. The variation in the concentration of high molecular weight kininogen (HK) showed effects on FXIIa and KRN that were qualitatively similar to those seen on variation of PKRN but 100% HK-deficient plasma generated considerable activities of both FXIIa and KRN. The variation in the concentration of factor XI (FXI) showed no effect on the generation of FXIIa, whereas KRN levels increased linearly with the contribution of FXI-deficient in normal plasma. The present results suggest that the contiguous binding of FXIIa, FXII, PKRN-HK and FXI-HK onto the electronegative surface induces a rapid generation of FXIIa and KRN. The bound PKRN-HK complex prevents the release of generated FXIIa and therefore further binding and activation of FXII from the bulk phase. Consequently, the turnover of FXII is independent of its levels in the bulk phase and is rather related to the concentration of contact surface. The generated KRN is also protected by HK. However, since the enzyme responsible for the activation of PKRN-HK is FXIIa, the levels of generated KRN are positively related to the concentration of substrate.
Transcriptional Expression of Tissue Factor Pathway Inhibitor, Thrombomodulin and von Willebrand Factor in Normal Human Tissues
Authors: Kuppuswamy M. N. , Manepalli A. N. , Bajaj S. P. , Bajaj M. S. 
Published: March 2018

SummaryUnder normal physiologic conditions, tissue factor pathway inhibitor (TFPI) is synthesized primarily by the microvascular endothelium. Using Northern blotting, we studied its transcriptional expression in different organs and compared it with the expression of two other endothelial specific proteins, namely thrombomodulin (TM) and von Willebrand factor (vWF). The order of mRNA expression for each protein was: TFPI–placenta>lung>liver>kidney>heart>skeletal muscle≥pancreas>brain; TM–heart>pancreas>lung>skeletal muscle>kidney≥liver>placenta>brain; and vWF–heart>skeletal muscle>pancreas>lung≥kidney>placenta>brain>liver. Notably, heart expressed TM and vWF mRNA in large amounts and only small amounts of TFPI whereas lung expressed all three mRNAs in significant amounts. Placenta, on the contrary, expressed large amounts of TFPI but only small amounts of TM and vWF mRNAs. Brain by this technique was found to express undetectable amounts of TFPI and TM mRNAs but small amounts of vWF mRNA. The expression of TFPI mRNA in the brain was however detected by RT/PCR and the antigen was localized to the endothelium of microvessels as well as to the astrocytes and oligodendrocytes. Since ultimate expression of proteins is linked to the expression of their mRNAs, our data support a concept that vascular endothelium is made up of phenotypically diverse groups of cells and that endothelial cells of different vascular beds express specific sets of genes that enable them to carry out tissue-specific functions. Importantly, since astrocytes are known to express tissue factor, the TFPI expression by these cells may control coagulation in their microenvironment and their response to injury and inflammation.
Inconsistency of Association between Type 1 von Willebrand Disease Phenotype and Genotype in Families Identified in an Epidemiological Investigation
Authors: Eikenboom Jeroen , Bertina Rogier , Rodeghiero Francesco , Castaman Giancarlo 
Published: March 2018

SummaryIn a previous epidemiological investigation among schoolchildren of Northern Italy, a conservative 1% prevalence of type 1 von Willebrand disease (VWD) was found. Diagnosis was based on a positive family history and low von Willebrand factor (VWF) ristocetin cofactor activity. To investigate whether the type 1 VWD phenotype as detected by our original methodology cosegregates with one or more specific alleles of the VWF gene, we have performed genotype analysis in affected subjects and their family members.Eleven of the 14 subjects previously identified as having VWD, all with mild personal bleeding symptoms, agreed to participate in the genetic study. Remarkably, the laboratory measurements of the previous investigation were completely confirmed in 10 of the 11 subjects. Clear cosegregation of the VWD type 1 and a specific VWF allele was observed in one family and was likely in the family of two other pro-bands. In three additional propositi and their families a possible association of the phenotype with a VWF allele was found. No association was observed in the remaining five subjects and their families. During 13-year follow-up few additional bleeding episodes were recorded among investigated subjects, most often occurring in the one family manifesting clear cosegregation.The results of this study illustrate that a personal and family bleeding history and persistently low VWF ristocetin cofactor activity, fitting the usual criteria for type 1 VWD, may not cosegregate with genetic markers at the VWF gene locus. Thus the prevalence of VWD defined as a disorder involving the VWF locus might be overestimated in population study. However, phenotypic diagnosis still remains fundamental to identify patients at risk of bleeding. Further research should clarify whether in families with more severe clinical and laboratory phenotype a clear association with markers of VWF is found.