bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging Venous Thromboembolism with Emphasis on Ultrasound, Chest CT, Angiography and Echocardiography
Authors: Torbicki Adam 
Published: March 2018

IntroductionThe clinical diagnosis of venous thromboembolism (VTE) is dif ficult and sometimes unreliable. Pulmonary angiography and contrast venography are used as reference tests for pulmonary embolism (PE) and deep vein thrombosis (DVT), respectively.1,2 However, due to the invasive nature of these reference tests, the optimal and clinically acceptable diagnosis of VTE remains a matter of some debate. Until recently, standard diagnostic strate gy in suspected pulmonary embolism (PE) consisted of a lung perfusion scan, followed by venous ultrasound (VUS), if a lung perfusion scan did not produce a definitive diagnosis. Eventually pulmonary angiography was performed.3,4 In clinical practice this strategy has rarely been respected because it required many pulmonary angiographic examinations. Diagnostic managemen was often halted prematurely without performing pulmonary angiography and, thus, without final confirmation or exclusion o PE.5-7 In addition, suspected DVT is often managed only on the basis of single VUS examination, which, unfortunately, has a rel atively low sensitivity when used to visualize the vasculature below the knee.8
This chapter focuses on newer, noninvasive diagnostic tests that permit direct imaging of venous thromboemboli. While the place of those tests in diagnostic algorithms remains to be fully determined, they may already be helpful in simplifying the diagnostic management of patients in many clinical situations including those patients at high-risk of venous thromboem bolism. These patients represent a non-homogeneous group such as patients with recent major surgery, serious medical dis eases, or a concomitant history of VTE or thrombophilia According to a recent consensus statement, screening for VTE is technically possible, but, in the presence of effective prophy laxis, neither was demonstrated to be necessary or cost effec tive.9 Therefore, the main effort should be focused on effective diagnostic management of those patients who present with symptoms and/or signs suggestive of VTE.
Factor X Levels, Polymorphisms in the Promoter Region of Factor X, and the Risk of Venous Thrombosis
Authors: Poort Swibertus , Vos Hans , Rosendaal Frits , Bertina Rogier , de Visser Marieke 
Published: March 2018

SummaryElevated levels of procoagulant proteins factor II, factor VIII, factor IX, factor XI and fibrinogen are associated with an increased risk of venous thrombosis. In a population-based case-control study on venous thrombosis (Leiden Thrombophilia Study, LETS) we investigated whether elevated coagulation factor X (FX) levels are a risk factor for venous thrombosis and whether FX levels are determined by polymorphisms in the promoter region of the FX gene. We found that subjects with high FX levels (above the 90th percentile, ≥ 126 U/dl) had a 1.6-fold increased risk of venous thrombosis. The highest risk (OR = 4.3, 95% confidence interval: 1.5-12) was found in the subgroup of premenopausal women who are not using oral contraceptives. However, these estimated risks disappeared after adjustment for other vitamin K-dependent coagulation factors II, VII and IX. To study the influence of genotypic variation on plasma FX levels we assessed four polymorphisms in the promoter region of the FX gene: a TTGTGA insertion between position -343A and -342G, a C/T polymorphism at position -222, a C/A polymorphism at position -220 and a C/T polymorphism at position -40. No relationship between these investigated genotypes and FX levels was observed. We conclude that high FX levels predict risk of thrombosis, but are not a risk factor for venous thrombosis when the levels of other vitamin K-dependent proteins are taken into account.
Ectopic αIIbβ3 Integrin Signaling Involves 12-Lipoxygenaseand PKC-mediated Serine Phosphorylation Events in Melanoma Cells
Authors: Rásó Erzsébet , Tóvári József , Tóth Krisztina , Paku Sándor , Trikha Mohit , Honn Kenneth , Tímár József 
Published: March 2018

SummaryMegakaryocytic genes such as αIIbβ3 can be expressed by malignant cells as part of the disturbances in their gene regulation. However, the function of the gene product greatly depends on the interaction of the ectopic protein with the new environment. The outside-in signaling of the ectopically expressed αIIbβ3 integrin was studied in B16a murine melanoma cells using a monoclonal antibody, specifically directed to the activated conformation of αIIbβ3, PAC-1 and the physiological ligand, fibrinogen. Ligation of αIIbβ3 induced downregulation of FAK but serine phosphorylation of three protein bands, 20/21, 85 and 140 kDa within 1-15 min. Flow cytometry indicated that the ligation of the receptor in B16a cells induces ~50% increase in phosphoserine positive cells within 5-15 min. 12-lipoxygenase is placed downstream in the signaling pathway, since ligation of αIIbβ3 induces 12-HETE production within 5 min and pretreatment of tumor cells with select lipoxygenase inhibitior, Baicalein, prevents the increase in serine phosphorylation. Confocal microscopy of adherent tumor cells demonstrated rearrangement of actin filaments upon αIIbβ3 ligation paralleled by downregulation of p125FAK and phoshotyrosine+ adhesion plaques and translocation of PKCα to stress fibers and cortical actin. PKC appears to be the major effector serine kinase of the αIIbβ3-coupled signaling pathway, since pretreatment of tumor cells with a select PKC inhibitor, Calphostin C, prevents the ligationinduced serine phosphorylation. Previous studies have indicated a role for the 12-lipoxygenase-PKC signaling pathway in platelet aggregation as well as tumor invasion, therefore the involvement of this cascade in the signaling of the ectopic αIIbβ3 integrin may partially explain its role in tumor progression.
The Role of Factor XI in Thrombin Generation Induced by Low Concentrations of Tissue Factor
Authors: Keularts Irene , Zivelin Ariella , Seligsohn Uri , Hemker H. Coenraad , Béguin Suzette 
Published: March 2018

SummaryThrombin generation has been studied in the plasma of severely factor XI deficient patients under conditions in which contact activation did not play a role. In platelet-rich as well as platelet-poor plasma, thrombin generation was dependent upon the presence of factor XI at tissue factor concentrations of between 1 and 20 pg/ml i.e. ~ 0.01 to 0.20% of the concentration normally present in the thromboplastin time determination. The requirement for factor XI is low; significant thrombin generation was seen at 1% factor XI; at 10%, thrombin formation was nearly normalised. A suspension of normal platelets in severely factor XI deficient plasma did not increase thrombin generation. This implies that there is no significant factor XI activity carried by normal platelets, although the presence of factor XI and factor XI inhibitors in platelets cannot be ruled out.
A Collaborative Study to Establish the 6th International Standard for Factor VIII Concentrate
Authors: Heath A. B. , Barrowcliffe T. W. , Raut S. 
Published: March 2018

SummaryA study was carried out to replace the 5th WHO International Standard (IS) for factor VIII concentrate, because of depletion of stocks. Two candidate concentrates (X and Y) were assayed as potential replacements against the 5th IS for FVIII concentrate, in a collaborative study involving 33 laboratories. Collaborators were asked to use the ISTH/SSC recommendations, including pre-dilution of concentrates in FVIII deficient plasma in their assays. Several laboratories performed more than one assay method and altogether there were 21 sets of assays with the one-stage method, 6 with the two-stage method and 26 with the chromogenic method. There was good agreement between laboratories using each method for the comparison of concentrates X and Y against the 5th IS, but the overall potencies by one-stage and chromogenic methods each differed by approximately 5% from the overall mean, with the chromogenic potency approximately 10% higher than the one-stage. Inter-laboratory agreement was slightly better for concentrate Y than X, and stability studies indicated that Y was more stable than X. After considering all the information, together with comments from participants and from the FVIII/FIX Subcommittee of the ISTH/SSC, candidate Y (NIBSC code [97/616]), was proposed and accepted in October, 1998, by the Expert Committee on Biological Standardisation of the World Health Organisation to be the 6th International Standard for Factor VIII Concentrate with an assigned potency of 8.5 IU/ampoule.
A Prospective Evaluation of the Interleukin-1 Receptor Antagonist Intron 2 Gene Polymorphism and the Risk of Myocardial Infarction
Authors: Lunze Karsten , Lindpaintner Klaus , Ridker Paul , Zee Robert 
Published: March 2018

SummaryWhile an interleukin-1 receptor antagonist gene polymorphism (IL1RN-VNTR) has recently been hypothesized to be a risk factor for coronary artery disease, no prospective data relating this polymorphism to subsequent risk of coronary events are available. We therefore investigated the association between IL1RN-VNTR genotype and the incidence of myocardial infarction (MI) in a large, prospective cohort of initially healthy men. The IL1RN-VNTR was evaluated among 385 MI case subjects and an equal number of age- and smoking-matched control subjects during a 12-year follow-up. Overall, the allele and g enotype distributions were similar among cases and controls, both in the total cohort and in all subgroups evaluated. All observed genotype frequencies were in Hardy-Weinberg equilibrium. Furthermore, the relative risk in a comparison of homozygous mutant to homozygous wild-type was 0.89 (95%CI = 0.5-1.6; P = 0.9). In this large, prospective study, the IL1RN-VNTR gene polymorphism is not associated with risks of future MI. These data also highlight the importance of hypothesis testing studies in genetic epidemiology, particularly for hypotheses generated from small samples or post hoc subgroup analyses.
Thrombostatin Inhibits Cyclic Flow Variations in Stenosed Canine Coronary Arteries
Authors: Hasan Ahmed , Warnock Mark , Normolle Daniel , Driscoll Edward , Lucchesi Benedict , Werns Steven , Schmaier Alvin 
Published: March 2018

SummaryThrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit -thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin’s active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t½α was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing γ-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i. v., clopidogrel 0.5 mg/kg i. v., or MAP4-RPPGF 0.77 mg/kg i. v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.
High Affinity Binding of Heparin by Necrotic Tumour Cells Neutralises Anticoagulant Activity
Authors: Morita Sumihito , Gebska Milena , Kakkar Ajay , Scully Michael 
Published: March 2018

SummaryWe have observed a striking neutralisation of the anticoagulant activity of unfractionated heparin in the presence of a pancreatic carcinoma cell line (MIA PaCa-2) due to binding of around 9 g of heparin per 107 cells (apparent Kd, 30 nM). The loss of anticoagulant activity was less marked in the presence of low molecular weight forms of heparin. Binding to the cell blocked acceleration of the thrombin:anti-thrombin interaction by heparin. Neutralisation of heparin activity was also shown to occur in the presence of a number of other tumour cell lines. FACS analysis demonstrated that live cells did not bind heparin and high affinity binding only occurred to dead MIA PaCa-2 cells. Heparin binding proteins accumulating in cell medium were identified as histone and ribosomal proteins that will become exposed during necrosis. The release of these proteins from cells within the necrotic core of a tumour or from cells killed during chemotherapy may abrogate the heparan sulphate/antithrombin system and possibly contribute to the idiopathic thromboembolism often associated with cancer (Trousseau’s syndrome). The findings also suggest a reason for the reported advantage of LMWH over UFH in treating venous thromboembolism in cancer patients and in improving patient survival.
Glucose and Insulin Modulate the Capacity of Endothelial Cells (HUVEC) to Express P-selectin and Bind a Monocytic Cell Line (U937)
Authors: Chettab Kamal , Duhault Jacques , Koenig-Berard Elisabeth , McGregor John , Puente Navazo Marta 
Published: March 2018

SummaryDiabetes mellitus is associated with increased prevalence of endothelial cell dysfunction and vascular diseases. Mechanisms leading to alterations in endothelial cell function are poorly understood. We report here that hyperglycaemia results in the expression of endothelial adhesion molecules involved in leukocyte adhesion and extravasation. Incubation of human umbilical cord endothelial cells (HUVEC) with 25 mM glucose induced the expression of P-selectin. This effect was reversed by the addition of 1 nM insulin. Moreover, increased ICAM-1 expression was observed upon HUVEC incubation with 25 mM glucose. Increased adhesion of U937 cells (a monocytic cell line) to endothelial cells cultured with 25 mM glucose was observed. High glucose-induced monocytes cell adhesion was inhibited by an anti-P-selectin monoclonal antibody (LYP20). These results show that high glucose concentration activates endothelial cells leading to monocytes adhesion providing further evidence that hyperglycaemia might be implicated in vessel wall lesions contributing to diabetic vascular disease.Present address: Dr. M. D. Puente Navazo, Centre Pluridisciplinaire d’Oncologie, ISREC, Epalinges, Switzerland
Synergistic Induction of t-PA by Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor and Localization of t-PA to Weibel-Palade Bodies in Bovine Microvascular Endothelial Cells
Authors: Rosnoblet Corinne , Sanza Corinne Di , Kruithof Egbert , Pepper Michael 
Published: March 2018

SummaryEndothelial cell migration is stimulated by members of the vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) families, and is dependent on extracellular proteolytic activity provided by enzymes of the plasminogen activator (PA) system. Here we report that in bovine microvascular endothelial cells (BME cells), bFGF principally increased urokinase-type PA (u-PA) while tissue-type PA (t-PA) was increased mainly by VEGF. In bovine aortic endothelial cells (BAE cells), bFGF increased u-PA, whereas VEGF had no effect. Co-added bFGF and VEGF increased t-PA mRNA levels and enzyme activity in both cell types in a synergistic manner. Tissue-type plasminogen activator (t-PA) immunoreactivity colocalized with von Willebrand factor, a marker for Weibel-Palade bodies. Co-added bFGF and VEGF increased the number of t-PA-positive cells as well as the number of t-PA-positive granules per cell. Localization of t-PA in regulated storage granules endows endothelial cells with the potential to rapidly increase proteolytic activity in the pericellular environment.
Protein Z-Dependent Regulation of Coagulation
Authors: Broze George 
Published: March 2018

SummaryProtein Z (PZ) is a 62 kDa vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by protein Z-dependent protease inhibitor (ZPI). ZPI is a recently identified 72 kDa member of the serpin superfamily of proteinase inhibitors that contains a tyrosine at its reactive center. PZ circulates in plasma in a complex with ZPI. Inhibition of factor Xa by ZPI in the presence of phospholipids and Ca++ is enhanced 1000-fold by PZ, but ZPI also inhibits factor XIa in a process that does not require PZ, phospholipids or Ca++. ZPI activity is consumed during coagulation through proteolysis mediated by factor Xa with PZ and factor XIa. Concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor VLeiden mice. Studies to determine the potential roles of PZ and ZPI deficiency in human thrombosis are in progress.
Role of Coagulation Inhibitors in Inflammation
Authors: Esmon Charles 
Published: March 2018

SummaryIt is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response.The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFκB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. colimediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
Von Willebrand Factor Propeptide in Vascular Disorders
Authors: Wit Thalia Romani de , van Mourik Jan 
Published: March 2018

SummaryVon Willebrand factor (VWF) is a multifunctional plasma protein that plays a prominent role in haemostasis. In endothelial cells, processing of its precursor pro-VWF results in the formation of two large polypeptides, mature VWF and a propeptide. These proteins are co-secreted on an equimolar basis but are cleared from the circulation at different rates. VWF levels are frequently elevated in response to vascular disorders. Similarly, propeptide levels are increased under these conditions, although primarily in fulminant vascular disease, such as thrombotic thrombocytopenic purpura and septicemia. In chronic vascular disease, e.g. diabetes or peripheral vascular disease, propeptide levels are much less elevated. The differential response of VWF and propeptide levels to vascular disease could provide a means to assess the extent and time course of endothelial cell activation. After secretion, the propeptide may play a role in modulating cellular adhesion processes. Thus, enhanced propeptide secretion seems not to be of merely diagnostic significance.
Platelet Collagen Receptors
Authors: Clemetson Jeannine , Clemetson Kenneth 
Published: March 2018

SummaryCollagens are important platelet activators in the vascular subendothelium and vessel wall. Since the regulation of platelet activation is a key step in distinguishing normal haemostasis from pathological thrombosis, collagen interactions with platelets are important targets for pharmacological control. Platelets have two major receptors for collagens, the integrin α2 β1, with a major role in adhesion and platelet anchoring and the Ig superfamily member, GPVI, principally responsible for signalling and platelet activation. In addition, GPIb-V-IX, can be considered as an indirect collagen receptor acting via von Willebrand factor as bridging molecule and is essential for platelet interactions with collagen at high shear rates. There is some evidence for additional receptors, which may regulate the response to individual collagen types. This review discusses how these receptors work separately with specific agonists and proposes possible mechanisms for how they work together to regulate platelet activation by collagen, which remains controversial and poorly understood.
A Journey with Platelet P-Selectin: The Molecular Basis of Granule Secretion, Signalling and Cell Adhesion
Authors: Furie Barbara , Flaumenhaft Robert , Furie Bruce 
Published: March 2018

SummaryP-selectin is a transmembrane protein that resides within the alpha granule membrane of unstimulated platelets. The “extracellular” domains face into the lumen of the granule and the cytoplasmic tail extends into the platelet cytoplasm. Upon platelet stimulation, P-selectin is phosphorylated and translocated to the plasma membrane via a secretory pathway. P-selectin in the plasma membrane surface is exposed and serves as a cell adhesion receptor to interact with other cell receptors, including PSGL-1 and GPIb. P-selectin upregulates tissue factor in monocytes and leads to leukocyte accumulation in areas of vascular injury associated with thrombosis and inflammation.
Hemostatic Risk Factors for Atherothrombotic Disease: An Epidemiologic View
Authors: Folsom Aaron 
Published: March 2018

SummaryA number of prospective epidemiologic studies have now tested the hypothesis that plasma measures of hemostatic factors measured in initially healthy subjects may predict the future onset of atherothrombotic events. Epidemiologic evidence is very strong that plasma fibrinogen is a risk marker, if not a causal factor, for atherothrombotic events. Evidence is mixed on whether factor VII, factor VIII, von Willebrand factor, or other coagulation markers predict incident atherothrombosis. D-dimer is emerging as a strong risk marker, as are several fibrinolytic markers such as tPA antigen – but not PAI-1. Despite suggestive studies, no genetic polymorphism influencing hemostatic factor levels has emerged as a consistent and strong risk factor for atherothrombosis. Thus, prospective epidemiologic studies have identified several potential hemostatic markers of atherothrombosis risk, but their causal role and clinical utility in risk prediction remain incompletely established.
Annexins: Key Regulators of Haemostasis, Thrombosis, and Apoptosis
Authors: Reutelingsperger Chris 
Published: March 2018

SummaryAnnexins form a family of proteins on the basis of structural and functional criteria. Their physiological relevance is still not fully understood, but is thought to involve phospholipid membrane associated processes. Recent data shed clues about their function in the regulation of thrombosis, haemostasis and apoptosis. These data arise from a multitude of physicochemical, cell biological, animal and clinical studies. This review presents this data and discusses them in the light of the novel understanding that apoptotic cells can contribute to thrombotic and haemostatic processes.