bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Performance Evaluation of Commercial Fibrinogen Reference Preparations and Assays for Clauss and PT-derived Fibrinogen
Authors: Lawrie A. S. , Kitchen S. , Gaffney P. J. , Howarth D. , Lowe G. D. O. , Martin J. , Purdy G. , Rigsby P. , Rumley A. , Mackie I. J. 
Published: March 2018

SummaryThe wide availability of fibrinogen estimations based on the prothrombin time (PT-Fg) has caused concern about the variability and clinical utility of fibrinogen assays. In a multi-centre study, we investigated fibrinogen assays using various reagents and analysers. Clauss assays generally gave good agreement, although one reagent gave 15–30% higher values in DIC and thrombolysis. Two commercial reference preparations had much lower potencies than the manufacturers declared, and plasma turbidity influenced parallelism in some Clauss assays. PT-Fg assays gave higher values than Clauss and showed calibrant dependent effects, the degree of disparity correlating with calibrant and test sample turbidity. Analyser and thromboplastin dependent differences were noted. The relationship between Clauss and PT-Fg assays was sigmoid, and the plateau of maximal PT-Fg differed by about 2 g/l between reagents. ELISA and immunonephelometric assays correlated well, but with a high degree of scatter. Antigen levels were higher than Clauss, but slightly lower than PT-Fg assays, which appeared to be influenced by degraded fibrinogen. Clauss assays are generally reproducible between centres, analysers and reagents, but PT-Fg assays are not reliable in clinical settings.
Enzyme immunoassay detection of platelet-derived microparticles and RANTES in acute coronary syndrome
Authors: Uehata Shigeru , Saito Sonoko , Osumi Kazuoki , Ozeki Yasushi , Kimura Yukio , Nomura Shosaku 
Published: March 2018

SummaryPlatelet-derived microparticles (PDMPs) are produced by platelet activation or physical stimulation under various conditions. To evaluate changes in platelet and chemokine function in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), we measured and compared levels of PDMPs and a C-C chemokine, regulated on activation normally T-cell express and secreted (RANTES), by ELISA. Levels of PDMP and RANTES in patients with acute coronary syndrome were significantly higher than those in the control groups (PDMP: 20.1 ± 2.9 vs 80.4 ± 7.3 U/ml, p < 0.001; RANTES: 18.6 ± 3.7 vs 52.1 ± 4.6 ng/ml, p < 0.01), but did not differ between the control groups and patients with stable angina. PDMP levels were higher in patients with acute myocardial infarction (AMI) than in patients with unstable angina (PDMP:115.0 ± 7.1 vs 63.9 ± 6.2 U/ml, p < 0.001). There was no difference in the RANTES levels, however, between patients with AMI and patients with unstable angina. PDMP and RANTES levels were significantly decreased after PTCA (PDMP, p < 0.001; RANTES, p < 0.05), but without differences between the two groups. In addition, the level of PDMP was significantly correlated with that of RANTES or soluble CD40 ligand. These findings suggest that PTCA may prevent the development of AMI-associated complications in which activated platelets and RANTES play roles. Our ELISA method appears to be sufficient for monitoring PDMP and RANTES levels after PTCA in patients with acute coronary syndrome.
Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence
Authors: Morange Pierre , Scarabin Pierre , Alessi Marie , Luc Gérald , Arveiler Dominique , Ferrieres Jean , Amouyel Philippe , Evans Alun , Ducimetiere Pierre , Juhan-Vague Irène ,   on behalf of the PRIME Study group
Published: March 2018

SummaryThrombin activatable fibrinolysis inhibitor (TAFI), a recently described inhibitor of fibrinolysis, has been hypothesized as playing a role in atherothrombosis. However, the evidence from retrospective studies, which have evaluated the role of TAFI in vascular risk, is conflicting.In a prospective cohort (the PRIME Study) of nearly 10 000 apparently healthy men recruited in France (Lille, Strasbourg, Toulouse) and Northern Ireland (Belfast), we measured baseline plasma concentration of TAFI antigen among 143 participants (81 from France and 62 from Ireland) who subsequently developed angina pectoris and among 286 age-matched participants who remained free of disease during the 5 years of follow-up. Genotyping of the Ala147Thr polymorphism located in the TAFI gene was performed using an allele specific PCR. In France, mean levels of TAFI were significantly higher at baseline among men who subsequently developed angina pectoris compared with their control subjects (119 versus 107 %; p = 0.02). The risk of future angina pectoris increased with increasing tertiles of TAFI (p = 0.02), such that men in the highest tertile at study entry had a 5-fold higher relative risk than those in the lowest tertile (95% confidence interval, 1.38 to 18.58) after controlling for the conventional cardiovascular risk factors. No such difference was observed in Northern Ireland. In France, Thr/Thr carriers of the Ala147Thr polymorphism were significantly more frequent in cases than in controls (p = 0.01) leading to a relative risk of angina pectoris of 2.7 (95%CI 1.2-5.8).Increase in plasma TAFI antigen levels is a risk factor for angina pectoris in France. Genotyping for the Ala147Thr polymorphism seems to be a reliable tool to assess the risk mediated by TAFI.
Fibrin-based biomaterials to deliver human growth factors
Authors: Wong Catalina , Inman Elisabeth , Spaethe Reiner , Helgerson Sam 
Published: March 2018

SummaryFibrin-based biomaterial preparations can be used as provisional growth matrices for cells important in tissue repair during wound healing in vivo. Their efficacy can be enhanced by including bioactive agents that promote specific cellular responses. This study examined the controlled delivery of the angiogenic growth factors bFGF, VEGF165, and VEGF121 using biomatrix preparations prepared from Fibrin Sealant product components. The growth factors were added prior to formation of the Fibrin Sealant clots, and the release kinetics of the proteins from the clots measured. The results indicated that the proteins were released from the clots more slowly in the order bFGF << VEGF165 < VEGF121. The biologic activity of the growth factors delivered from Fibrin Sealant clots was established by assaying growth stimulation of human microvascular endothelial cells (HMVEC) and angiogenesis in the chicken embryo chorioallantoic membrane (CAM) model of neovascularization. In the latter assay, clots containing bFGF, VEGF165, or V EGF121 all displayed angiogenic activity. However, delivery of either bFGF, VEGF165, or VEGF121 alone resulted in a significant percentage of clots becoming filled with blood, indicating that the newly developing vessels invading the clots were leaky and immature. In contrast, this hemorrhaging behavior did not occur with delivery of combinations, e.g., (VEGF165 + VEGF121) or (VEGF165 + bFGF), indicating that the vessels were more mature than those produced in response to single growth factors. Thus, delivering a combination of growth factors constituted an improvement over the delivery of individual growth factors for enhancing neovascularization.Part of this research was presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society held in Munich, Germany.
Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition
Authors: Schäfer Andreas , Fraccarollo Daniela , Hildemann Steven , Christ Michael , Eigenthaler Martin , Kobsar Anna , Walter Ulrich , Bauersachs Johann 
Published: March 2018

SummaryAn increased risk of thrombembolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and platelet activation.After experimental myocardial infarction, male Wistar rats were treated with placebo, the ACE inhibitor trandolapril, the selective aldosterone receptor antagonist eplerenone or the combination of both, for 10 weeks. Platelet-bound fibrinogen and surface-expressed P-selectin were not modulated in rats without CHF compared with sham-operated animals, but were significantly increased in CHF rats (LVEDP>15mmHg). In CHF rats, ACE inhibition significantly reduced platelet P-selectin expression while bound fibrinogen was not modulated. Eplerenone reduced P-selectin expression to a comparable extent, while platelet-bound fibrinogen was normalised. Combination therapy with eplerenone and trandolapril completely abolished both the increased P-selectin expression as well as fibrinogen binding. Phosphorylation of platelet vasodila-tor-stimulated phosphoprotein (VASP) at both Ser157 and Ser239, which reflects the activity of platelet inhibitors including nitric oxide, was significantly reduced in platelets from placebo-treated CHF rats, and was completely normalised by combination treatment, but only marginally increased by either mono-therapy.The results show that platelet activation was evident only in CHF rats. Monotherapy with ACE inhibition or eplerenone partially reduced this increased platelet activation, which was completely rescued to basal levels by combination therapy. Increased nitric oxide bioavailability can only partially explain the reduced platelet activation by eplerenone and ACE inhibition.
TNF 41-62 and TNF 78-96 Have Distinct Effects on LPS-induced Tissue Factor Activity and the Production of Cytokines in Human Blood Cells
Authors: Rekda Ø. , Svendsen J.S. , Østerud B. , Eliassen L.T. 
Published: March 2018

SummaryBiological activities of peptides representing two different regions in the TNF molecule were investigated. We have earlier reported that one of the peptides studied, TNF 36-62, induced chemotaxis in granulocytes and monocytes. TNF 41-62, a shorter analog of TNF 36-62, possessed similar chemotactic effects. Both peptides caused a weak enhancement of LPS -induced IL-6 production and tissue factor activity by monocytes in whole blood. The third peptide studied, TNF 78-96, was selected from a region located on the opposite side of the β-sheet sandwich structure of the TNF molecule, and includes the loop 84-88 that has been shown to be involved in TNF receptor interaction. TNF 78-96 possessed properties quite different from TNF 36-62 and TNF 41-62. It amplified several fold PMA-induced secretion of elastase, and enhanced significantly PMA-induced secretion of cathepsin G from the neutrophils, activities which were effectively abolished by an anti-human TNF antibody. The TNF 78-96 peptide also inhibited LPS-induced TF activity in monocytes of whole blood, and it abolished the TNF enhancing effect of LPS-induced TF activty in a dose dependent manner. This suggests that the TNF 78-96 peptide may bind to the TNF receptor(s), without potentiating the same signals as native TNF. It may thereby prevent binding of the native TNF and the resultant activation effect of TNF. It also, at high concentrations, inhibited LPS-induced IL-6 production whereas it caused a doubling of LPS-induced IL-8 in monocytes and granulocytes in whole blood. These results clearly show that distinct TNF activities can be induced by peptide sequences taken from different regions of TNF. The TNF 78-96 peptide might be useful in downregulation of LPS-induced monocyte activations in vivo.
Thrombopoietin Increases Platelet Sensitivity to α-Thrombin via Activation of the ERK2-cPLA2 Pathway
Authors: Gorter Gertie , Akkerman Jan-Willem , van Willigen Gijsbert 
Published: March 2018

SummaryThrombopoietin (TPO) regulates stem cell proliferation and maturation of megakaryocytes by activating the c-Mpl-receptor, a member of the hematopoietic cytokine family. As human platelets possess c-Mplreceptors and supraphysiological concentrations of TPO trigger platelet aggregation and secretion, we searched for the signalling pathways through which the c-Mpl-receptor might activate platelets. A physiological concentration of TPO (20 ng/mL) did not trigger platelet functions, but increased their sensitivity to α-thrombin resulting in a 4-fold faster dense granule secretion. The effect of TPO was abolished by indomethacin and caused by synergism with signal generation by α-thrombin at the level of the cytosolic phospholipase A2 (cPLA2) pathway resulting in more arachidonate release, cPLA2 phosphorylation and thromboxane A2 formation. A similar synergism was seen at the level of extracellular signal-regulated kinase 2 (ERK2 or p42-MAPK). These data suggest, that TPO increases the sensitivity of platelets to α-thrombin by enhancing cPLA2 activation via the ERK2-cPLA2 pathway.
Humanized Severe Combined Immunodeficient Mice as a Potential Model for the Study of Tolerance to Factor VIII
Authors: Vanzieleghem Beatrijs , Gilles Jean , Desqueper Benoît , Vermylen Jos , Saint-Remy Jean-Marie 
Published: March 2018

SummaryA Severe Combined Immunodeficient (SCID) mouse model has been established to evaluate experimental conditions leading to the production of factor VIII (FVIII) autoantibodies. To this end, we humanized 10 groups of 7 mice with peripheral blood mononuclear cells of 10 unrelated healthy blood donors (15 X 106 cells/mouse). Mice were injected with saline or immunized i.p. with 50 IU of a plasma derived human FVIII 24 h after reconstitution. Further immunization was made with 25 IU of FVIII every fortnight during 6 weeks and animals were sacrificed after 8 weeks. All reconstituted mice showed a spontaneous production of anti-FVIII antibodies in the absence of immunization with the corresponding antigen. However, no differences were observed regarding the quantity or the quality of these antibodies produced in the immunized or the saline group, indicating that tolerance to FVIII had been transferred with cell reconstitution. Affinity purified FVIII specific antibodies were capable of inhibiting FVIII activity and preventing the binding of FVIII to phospholipids in a dose-dependent manner. Immunoprecipitation experiments showed that the antibodies recognized only the C1 and C2 light chain domains. Since antibodies of interest can be found in the SCID mouse model and, moreover, since they are qualitatively comparable with the source donor’s antibodies, this model provides a tool to study the regulation of tolerance against self antigens in normal subjects and in acquired haemophilia patients.
Reduced Expression of Endothelial Cell Markers after Long-term Transdermal Hormone Replacement Therapy in Women with Coronary Artery Disease
Authors: Arnesen Harald , Hofstad Ann-Elin , Os Ingrid , Seljeflot Ingebjørg 
Published: March 2018

SummaryThe effects of 12 months hormone replacement therapy (HRT) on biochemical markers associated with endothelial function were studied in 98 postmenopausal women with CAD, who were randomized to transdermal HRT or a control group.A significant reduction in the levels of von Willebrand factor in the HRT-group compared to controls was seen after 3 months, maintained after 12 months (p <0.001). Significant reduction in the HRT-group compared to controls was also seen in VCAM-1 after 3 months, sustained after 12 months (p = 0.013 and p = 0.045, respectively), and E-selectin was reduced by about 20% after 3 months on HRT, the reduction being statistically significant after 12 months (p <0.001). Significantly reduced levels of ICAM-1 were also seen after 12 months (p = 0.048). No effects could be observed on tPA-antigen or thrombomodulin.The reduction in procoagulant and proinflammatory markers of endothelial function after long-term transdermal HRT could indicate a beneficial effect on the endothelium and thus a potentially modulating effect on the progression of atherosclerosis in women with CAD.
A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways
Authors: Tans Guido , Curvers Joyce , Middeldorp Saskia , Thomassen M. Christella , Prins Martin , Bouma Bonno , Büller Harry , Meijers Joost , Rosing Jan 
Published: March 2018

SummaryThe use of oral contraceptives (OC) causes disturbances of the procoagulant, anticoagulant and fibrinolytic pathways of blood coagulation which may contribute to the increased risk of venous thrombosis associated with OC therapy. Here we report the results of a cyclecontrolled randomized cross-over study, in which we determined the effects of so-called second and third generation OC’s on a number of anticoagulant parameters. In this study, 28 non-OC using women were randomly prescribed either a second generation (150 µg levonorgestrel/30 µg ethinylestradiol) or a third generation OC (150 µg desogestrel/30 µg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), α2-macroglobulin (α2-M), α1-antitrypsin, protein C inhibitor (PCI), protein C, total and free protein S and activated protein C sensitivity ratios (APC-sr) measured with two functional APC resistance tests which quantify the effect of APC on either the activated partial thromboplastin time (aPTT) or on the endogenous thrombin potential (ETP). During the use of desogestrel-containing OC the plasma levels of αc2-M, α1-antitrypsin, PCI and protein C significantly increased, whereas AT and protein S significantly decreased. Similar trends were observed with levonorgestrel-containing OC, although on this kind of OC the changes in AT, PCI and protein S (which was even slightly increased) did not reach significance. Compared with levonorgestrel, desogestrel-containing OC caused a significant decrease of total (p <0.005) as well as free protein S (p <0.0001) and more pronounced APC resistance in both the aPTT (p = 0.02) and ETPbased (p <0.0001) APC resistance tests. These observations indicate that the activity of the anticoagulant pathways in plasma from users of desogestrel-containing OC is more extensively impaired than in plasma from users of levonorgestrel-containing OC.
Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Polymorphism, Coronary Thrombosis, and Myocardial Infarction in Middle-aged Finnish Men who Died Suddenly
Authors: Perola Markus , Wartiovaara Ulla , Peltonen Leena , Palotie Aarno , Penttilä Antti , Karhunen Pekka , Mikkelsson Jussi 
Published: March 2018

SummaryHigh plasminogen activator inhibitor-1 (PAI-1) plasma levels increase future risk of myocardial infarction (MI). The 4G allele of the 4G/5G polymorphism of the PAI-1 gene has been associated with increased plasma levels of PAI-1. The association of the PAI-1 polymorphism with coronary narrowings, coronary thrombosis and myocardial infarction (MI) was studied in a prospective autopsy series of 300 middle-aged Caucasian Finnish men (33 to 69 yrs) suffering sudden out-of-hospital death (Helsinki Sudden Death Study). The 4G allele was found in 76.8% of men with sudden cardiac death (SCD) compared to 67.5% in men who died accidentally and 63.2% in men who died of other diseases (p = 0.08 and p = 0.055, respectively). Men possessing the 4G allele had more often acute MI (OR 3.5; p <0.05) and coronary thrombosis (OR 5.5; p = 0.01) compared to 5G homozygotes. 5G homozygotes, comprising one third of the men in our study, seem to be at a decreased risk of thrombosis, whereas carriers of the common 4G allele have an increased risk of thrombosis, AMI and possibly SCD compared to 5G homozygotes.
Identification of Eight Novel Single-Nucleotide Polymorphisms at Human Tissue-type Plasminogen Activator (t-PA) Locus: Association with Vascular t-PA Release In Vivo
Authors: Ladenvall Per , Wall Ulrika , Jern Sverker , Jern Christina 
Published: March 2018

SummaryRecently, we reported that an Alu insertion polymorphism of the tissue-type plasminogen activator (t-PA) gene is associated with vascular t-PA release rates in man. In the current study we searched the t-PA gene for putative functional genetic variants in linkage disequilibrium (LD) with this polymorphism. Healthy individuals with different Alu genotypes and contrasting t-PA release rates were studied. Regulatory and coding regions of the t-PA gene were sequenced. Eight singlenucleotide polymorphisms (SNPs) were identified. Three of these were in significant LD with the Alu polymorphism and consequently associated with t-PA release rates; one in the far upstream enhancer, one in exon 6, and one in intron 10. The enhancer SNP resides within a GC box. Electrophoretic mobility shift assay (EMSA) revealed a reduced binding affinity of Sp1 to the T allele, which is the allele associated with a low t-PA release rate. Variations in exon 6 and intron 10 were silent and without apparent effect on splicing, respectively.
A New T-287C Polymorphism in the 5’ Regulatory Region of the Tissue Factor Pathway Inhibitor Gene
Authors: Moatti Didier , Haidar Bassam , Fumeron Frédéric , Gauci Laurent , Boudvillain Olivier , Seknadji Patrick , Ollivier Véronique , Aumont Marie , de Prost Dominique 
Published: March 2018

SummaryTissue factor pathway inhibitor (TFPI) is an important regulator of the extrinsic blood coagulation pathway. We screened the untranslated 5’ region of the TFPI gene for polymorphisms and investigated their possible involvement in arterial thrombosis. The allele frequencies of a new polymorphism, located 287 base pairs upstream of the transcription start site (T-287C), and that of the previously described C-399T polymorphism, were similar in cases and controls. In controls, the -287C allele was associated with significantly higher levels of total TFPI antigen, arguing for an effect of this polymorphism on TFPI gene expression. In controls, the C-399T polymorphism did not alter TFPI levels. In the cases, however, decreased total and post-heparin free TFPI levels and increased F1+2 levels were significantly associated with the -399T allele. These findings suggest that the T-287C and C-399T polymorphisms are not associated with an increased risk of coronary heart disease, a result which should be confirmed by a larger study. However, their influence on outcome, or a link with subtypes of acute coronary syndromes, cannot be excluded.