bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis
Authors: Aimes Ronald , Zijlstra Andries , Hooper John , Ogbourne Steven , Sit Mae-Le , Fuchs Simone , Gotley David , Quigley James , Antalis Toni 
Published: March 2018

SummaryMany serine proteases play important regulatory roles in complex biological systems, but only a few have been linked directly with capillary morphogenesis and angiogenesis. Here we provide evidence that serine protease activities, independent of the plasminogen activation cascade, are required for microvascular endothelial cell reorganization and capillary morphogenesis in vitro. A homology cloning approach targeting conserved motifs present in all serine proteases, was used to identify candidate serine proteases involved in these processes, and revealed 5 genes (acrosin, testisin, neurosin, PSP and neurotrypsin), none of which had been associated previously with expression in endothelial cells. A subsequent gene-specific RT-PCR screen for 22 serine proteases confirmed expression of these 5 genes and identified 7 additional serine protease genes expressed by human endothelial cells, urokinase-type plasminogen activator, protein C, TMPRSS2, hepsin, matriptase/ MT-SP1, dipeptidylpeptidase IV, and seprase. Differences in serine protease gene expression between microvascular and human umbilical vein endothelial cells (HUVECs) were identified and several serine protease genes were found to be regulated by the nature of the substratum, ie. artificial basement membrane or fibrillar type I collagen. mRNA transcripts of several serine protease genes were associated with blood vessels in vivo by in situ hybridization of human tissue specimens. These data suggest a potential role for serine proteases, not previously associated with endothelium, in vascular function and angiogenesis.
Fibrin(ogen) in cardiovascular disease: an update
Authors: Koenig Wolfgang 
Published: March 2018

SummaryThe notion that fibrinogen is strongly, consistently, and independently related to cardiovascular risk has been widely accepted. The evidence is based on numerous prospective epidemiological studies and clinical observations. In meta-analysis, an association between even modest increases (10%) in fibrino-gen and future coronary heart disease (CHD) endpoints has been found with an odds ratio for CHD of 1.8; 95% CI, 1.6 to 2.0, if the top tertile of the fibrinogen distribution was compared to the bottom tertile; but fibrinogen levels were also associated with unstable and stable coronary artery disease, and coronary complications after interventions. Similar results have been obtained for incident stroke, progression of peripheral arterial disease, and finally for total mortality. The reasons however, why fibrinogen is elevated in cardiovascular disease and in atherosclerosis in general, are only incompletely under-stood; but all cells involved in the atherogenetic process are able to produce cytokines which induce an acute phase reaction, and thus increase fibrinogen plasma levels. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are manyfold: It forms the substrate for thrombin and represents the final step in the coagulation cascade; it is essential for platelet aggregation; it modulates endothelial function;it promotes smooth muscle cell proliferation and migration; it interacts with the binding of plas-min with its receptor, and finally it represents a major acute phase protein. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined, and even though other unsolved issues await conclusive answers, fibrino-gen has emerged as an important additional marker of cardiovascular risk.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.
Molecular and cellular modulation of fibrinolysis
Authors: Kolev Krasimir , Machovich Raymund 
Published: March 2018

SummaryThe structure of the fibrin network, the hemodynamic environment of the clot, the kinetic properties of the fibrinolytic enzymes and the balance of their formation and inactivation essentially determine the effectiveness of fibrinolysis in vivo. The fibrin structure and the action of proteases, however depend considerably on additional, apparently inert physiological and pathological factors, which are restricted to more or less transient compartments in fluid-solid interface, such as thrombus (fibrin with platelet membrane structures), endothelial cell surface, the environment of polymorphonuclear cells (PMN). In these compartments extreme changes in concentrations and rate enhancements are observed. Components released by endothelial cells, PMNs and platelets or molecules present in circulating blood create a heterogeneous milieu that modulates fibrinolysis. This review summarizes the effects, and where it is possible, explains the mechanism of modulators of the fibrinolytic processes, such as cell membrane and cellular contents of endothelium, PMN and platelets present in thrombi, the action of normal and pathological blood plasma- and extracellular matrix-components.
Monitoring of Aspirin (ASA) Pharmacodynamics with the Platelet Function Analyzer PFA-100®
Authors: Homoncik Monika , Hergovich Nicole , Stohlawetz Petra , Panzer Simon , Speiser Wolfgang , Jilma Bernd 
Published: March 2018

SummaryAnti-platelet drug therapy is currently performed without monitoring, because the established method of platelet aggregometry is cumbersome. The recently developed platelet function analyzer PFA-100® measures shear stress dependent, collagen epinephrine (CEPI) and collagen adenosine diphosphate (CADP) induced platelet plug formation. As the PFA-100 provides a valuable tool to detect patients with platelet dysfunction more efficiently and cost-effectively than aggregometry, we investigated its potential to monitor the efficacy of aspirin treatment.All healthy volunteers (n = 10) received a fractionated infusion of L-aspirin to establish individual dose-response curves. Further, in a randomized, double-blind, placebo controlled two-way cross over study the same volunteers received either 50 or 100 mg aspirin/day p.o. for a period of 11 days to determine the day-to-day variability CEPI induced closure time (CT) under constant intake of low dose aspirin, and to compare the efficacy of those two doses.Intra- and intersubject variability of CEPI-CT averaged 9% and 22%, respectively. Seven volunteers exceeded the maximum of CEPI-CT (>300 s) already after infusion of 100 mg L-aspirin. Intake of 100 mg of aspirin elicited a more rapid onset of effect than 50 mg, which was only significant on days 3 and 4 of aspirin intake. The aspirin induced CEPI-CT prolongation correlated positively with basal CEPI-CT values (r = 0.86; p = 0.001) and were strongly dependent on von Willebrand Factor levels (r = -0.9; p = 0.001).Thus, the PFA-100 system appears suitable to demonstrate an aspirin-induced platelet effect in a longitudinal study, and may be adequate to monitor a patient’s compliance. However, prospective trials have to be conducted to demonstrate whether the EPI-CT achieved under ASA-intake has predictive value for cardiovascular outcome.
Regional Variation in Plasminogen Activator Inhibitor-1 Expression in Adipose Tissue from Obese Individuals
Authors: Van Harmelen Vanessa , Hoffstedt Johan , Lundquist Per , Vidal Hubert , Stemme Veronika , Hamsten Anders , Arner Peter , Reynisdottir Signy , Eriksson Per 
Published: March 2018

SummaryHigh plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 ± 50 vs 138 ± 24 ng PAI-1/107 cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 ± 0.37 vs 0.81 ± 0.12 attomole PAI-1 mRNA/µg total RNA, P <0.001). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P <0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.
The HR2 Haplotype of Factor V: Effects on Factor V Levels, Normalized Activated Protein C Sensitivity Ratios and the Risk of Venous Thrombosis
Authors: Guasch Joan , Kamphuisen Pieter , Vos Hans , Rosendaal Frits , Bertina Rogier , de Visser Marieke 
Published: March 2018

SummaryWe studied the HR2 haplotype of the factor V gene in a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched healthy controls (Leiden Thrombophilia Study, LETS). We investigated both the original His1299Arg (A4070G) polymorphism and the Met385Thr (T1328C) polymorphism. This latter polymorphism, located in exon 8 (heavy chain), is always present in the HR2 haplotype, but also occurs on its own in a His1299 (wt) background. The HR2 haplotype was not associated with an increased risk of venous thrombosis (OR = 1.2, 95% confidence interval: 0.8-2.0). We did not find an association between the HR2 haplotype and a reduced sensitivity for activated protein C (APC) in non-carriers of factor V Leiden (FVL). However, in compound heterozygous FVL/HR2 carriers the sensitivity for APC was reduced. The HR2 haplotype was also associated with reduced factor V antigen levels in both patients and controls. Sequence analysis of the promoter region of factor V in HR2 homozygotes did not reveal any sequence variations that could explain the reduced FV levels. Our results show that the HR2 haplotype is not associated with an increased risk of venous thrombosis or with a reduced sensitivity for APC in non-FVL carriers. However, the HR2 haplotype is associated with a reduced sensitivity for APC in carriers of FVL and with reduced factor V antigen levels.
Prevalence of Factor V Leiden in Patients with Myocardial Infarction and Normal Coronary Angiography
Authors: Da Costa Antoine , Munier Stéphane , Mercier Bernard , Tardy Brigitte , Ferec Claude , Isaaz Karl , Blanc Jean-Jacques , Mansourati Jacques 
Published: March 2018

SummaryFactor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography.We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls.Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95 : 1.18-7.31) and 2.63 (CI95 : 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis.In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.
A Computer Generated Induction System for Hospitalized Patients Starting on Oral Anticoagulant Therapy
Authors: Johnson Judith , Nowacki Barbara , Turpie Alexander , Ageno Walter 
Published: March 2018

SummaryThere is an increasing use of computer-based dosage programs to monitor oral anticoagulant therapy in outpatients. DAWN AC INDUCTION by 4S, UK, is a computer generated system to initiate oral anticoagulant therapy providing fast access to the maintenance program. This method of initiation of anticoagulant therapy has not been validated. We therefore randomized 50 hospitalized patients starting oral anticoagulation to control by the computer and 51 by manual dosing using a dosing schedule based on a locally defined algorithm. After a 7 days follow up, the daily mean INR was 2.09 and 2.07 and the proportion of dose adjustments was 48% and 45% in the computer and manually controlled groups respectively. Twenty-eight % of the patients monitored by the computer system required at least one manual overriding. DAWN AC INDUCTION provided a simple and accurate organization of the data, with an overall quality comparable to that of the manual system. Furthermore, the induction programme provided simple access to the maintenance programme. Although it required careful monitoring, the programme resulted in a significant saving in personnel time.
Induction of Tissue Factor Expression in Whole Blood: Lack of Evidence for the Presence of Tissue Factor Expression in Granulocytes
Authors: Østerud Bjarne , Olsen Jan , Rao L. Vijaya 
Published: March 2018

SummaryThe present investigation was undertaken to explore the effect of platelets, tumor necrosis factor (TNF) and phorbel ester [phorbol 12-myristate 13-acetate (PMA)] on lipopolysaccharide (LPS)-induced tissue factor (TF) activity and TF antigen by using Western blot and ELISA-techniques. LPS was found to induce correlating levels of TF antigen and the activity in monocytes. TNF and PMA, when used alone, failed to induce TF activity and the antigen in monocytes, but enhanced the LPS-induced TF activity and the antigen by 2 to 3-fold. Addition of platelet rich plasma to isolated blood cells enhanced the LPS-induced TF activity but not the antigen levels in monocytes. In contrast to whole platelets, platelet lysates enhanced both LPS-induced TF activity and the antigen. Granulocytes isolated from heparinized plasma incubated for 2 or 24 h with LPS alone or together with PMA, failed to generate TF antigen or the activity. Although granulocyte preparations isolated from whole blood that was incubated for 24 h with LPS and PMA apparently possessed a significant amount of TF activity and the antigen, this could be accounted for by trace levels of contaminating monocytes. Upregulation of LPS-induced TF activity but not the antigen by platelets in the presence of granulocytes suggests that the increased TF activity could be the result of PS enrichment of monocytes by fusion or platelets with activated monocytes.
Plasma TAFI Antigen Variations in Healthy Subjects
Authors: Chetaille P. , Alessi M. C. , Kouassi D. , Morange P. E. , Juhan-Vague I. 
Published: March 2018

SummaryThe Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. The physiological variations of plasma TAFI antigen are not well known. We studied TAFI antigen values in healthy populations with a commercially available kit from Milan Analytica (Switzerland). Broad range of TAFI antigen values (from 41% to 259%) was found in a population of 249 healthy individuals. Gender as well as pregnancy did not influence mean values of TAFI antigen. There was a positive correlation between TAFI antigen and age in female (r = 0.28; p <0.05) but not in male populations. Mean TAFI antigen value of a black African male group [mean ± SD (range): 87 ± 23 (39-144%)] was significantly lower than the one of age matched Caucasian men [114 ± 34 (52-259%)] (p <0.0001). TAFI antigen values were very stable within individuals, they did not significantly vary on day time or at several months period.Thus, in contrast to large inter-individual variations, TAFI antigen levels are quite stable within individuals.
Effects on Coagulation of Levonorgestrel- and Desogestrel-containing Low Dose Oral Contraceptives: a Cross-over Study
Authors: Meijers Joost , van den Ende Abraham , van Enk Adam , Bouma Bonno , Tans Guido , Rosing Jan , Prins Martin , Büller Harry , Middeldorp Saskia 
Published: March 2018

SummaryCombined oral contraceptives (OC) are known to increase the risk of venous thromboembolism. The aim of this randomized, cycle-controlled, cross-over study in 28 healthy volunteers was to assess potential differences between the effects of an OC containing 150 µg levonorgestrel (as representative of the so-called second generation OC) and an OC containing 150 µg desogestrel (as representative of the third generation OC) in combination with 30 µg ethinylestradiol on several coagulation factors and markers of thrombin formation. All participants used each OC for two cycles, and were switched to the other OC after a washout period of two menstrual cycles. The plasma concentrations of factors II, VII, X, and fibrinogen significantly increased during use of both the levonorgestrel- and desogestrel-containing OC’s. The plasma concentrations of factor VIII increased, and of factor V decreased, changes which only reached statistical significance during the use of the desogestrel-containing OC. During exposure to the desogestrel-containing OC, as compared with the levonorgestrel-containing OC, both factor VII and factor II showed a greater increase (FVII: 32% and 12% respectively; p <0.0001; FII: 16% and 12% respectively; p = 0.048), whereas factor V showed a greater decrease (–11% and –3% respectively; p = 0.010). Only one of the markers for ongoing coagulation (prothrombin fragment 1+2) showed a significant increase during OC use, whereas concentrations of thrombin-antithrombin complexes and soluble fibrin remained unchanged. For these markers, there was no difference between the tested OC’s. We conclude that there are differences between the effects of levonorgestrel and desogestrel-containing OC’s on some coagulation factors. Whether these changes provide a biological explanation for the reported differences in venous thromboembolic risk is as yet unclear. The real challenge now becomes to define a pattern of changes in the various systems which, if affected simultaneously, may tip the hemostatic balance towards a prethrombotic state and may lead to overt clinical venous thromboembolism.
Rapid ELISA Assay for Plasma D-Dimer in the Diagnosis of Segmental and Subsegmental Pulmonary Embolism
Authors: van Ingen Huub , van Beek Edwin , Berghout Arie , Oudkerk Matthijs , Sijens Paul 
Published: March 2018

Summary
Study objective To assess the accuracy of a rapid ELISA D-dimer assay for the exclusion of pulmonary embolism (PE) in patients suspected of PE, using pulmonary angiography alone as reference method rather than a diagnostic strategy including lung scintigraphy and leg vein ultrasonography. Methods In 342 patients who were examined by pulmonary angiography to diagnose or exclude PE, the accuracy of the quantitative rapid VIDAS D-dimer test for the exclusion of PE was evaluated retrospectively. D-dimer levels were assayed in frozen samples collected during the diagnostic work-up at the time of pulmonary angiography while on treatment with unfractionated heparin for 1-2 days. Results Mean plasma D-dimer concentrations were increased in patients with angiographic evidence of PE (P <0.0001). The sensitivity of D-dimer for segmental PE was 98%, its accuracy in excluding segmental PE was 99%, higher than the respective figures for subsegmental PE (76% and 94%; P <0.01, both). For both forms of PE combined the sensitivity was 90% and the negative predictive value 94%. Discussion The sensitivity and negative predictive values reported here, are low compared with previous studies using the same rapid ELISA D-dimer assay. This probably reflects an overlooking of mild cases of subsegmental PE in previous studies, although a reduction of D-dimer levels by the heparin pretreatment may have contributed to part of the discrepancy. Prospective studies are needed to clarify this issue.
Acquired von Willebrand Syndrome: from Pathophysiology to Management
Authors: Veyradier Agnès , Jenkins Charles , Fressinaud Edith , Meyer Dominique 
Published: March 2018

SummaryAcquired von Willebrand syndrome (AvWS) is a rare and probably underestimated bleeding disorder which mimicks most of the clinical symptoms and laboratory features of hereditary von Willebrand disease (vWD) in patients devoid of both personal and familial history of bleeding diathesis (1). AvWS and congenital vWD both result from a defect in von Willebrand factor (vWF), a large multimeric glycoprotein present in megakaryocytes, platelets, endothelial cells, subendothelium and mainly in plasma (2). vWF is essential to platelet adhesion and aggregation at the site of vascular injury by acting as a bridge between platelet receptors and the collagen of the subendothelium as well as between platelets themselves. vWF binds to both platelet receptors glycoprotein (GP) Ib and GP IIb/IIIa and also to coagulation factor VIII (F.VIII) acting as a stabilizing carrier protein in plasma. The revised classification of hereditary vWD (3) includes three major types: type 1 and type 3 are respectively related to a partial or a total quantitative defect while type 2 (variants including several subtypes) results from a qualitative defect of vWF. Although vWD is well known to be the most common inherited bleeding disorder with a worldwide prevalence of 1 to 2% (1), more than 200 cases of AvWS have been reported since it was described in 1968 (4). It is likely, however, that this number is underestimated since isolated case-reports of AvWS tend to be less published and its diagnosis remains difficult. AvWS is most commonly found together with a variety of concurrent diseases which are mainly clonal hematoproliferative, neoplasia and autoimmune disorders (5-7). The pathophysiological basis of AvWS as well as its response to treatment depend clearly on the associated underlying disease. In this paper, we summarized all the situations where an AvWS may be observed as a function of the anamnestic and clinical data, the pathogenic mechanisms and the laboratory features. Moreover, we propose a therapeutic flow chart based on both data from the literature and personal experience.