bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abnormal Fibrin Clot Architecture in Nephrotic Patients Is Related to Hypofibrinolysis: Influence of Plasma Biochemical Modifications
Authors: Mishal Zohar , Lesty Claude , Mirshahi Manoucher , Peynet Jacqueline , Baumelou Alain , Bensman Albert , Soria Jeannette , Soria Claudine , Collet Jean-Philippe 
Published: March 2018

SummaryPorosity, viscoelasticity and morphological properties of plasma fibrin from 16 nephrotic patients and 16 healthy volunteers were compared. Nephrotic patients were characterized by formation of tight and rigid plasma fibrin gels which resulted in a slower rate of fibrin lysis studied either under pressure-driven permeation or diffusional transport of fibrinolytic agents. These latter findings indicated that both abnormal fibrin network conformation and abnormal fibrin fiber structure were involved in hypofibrinolysis. Albumin supplementation up to 40 mg/ml partially restored normal fibrin architecture and increased the rate of fibrinolysis in these patients. Multiparametric analysis showed that nephrotic patients were mainly characterized by a low plasma albumin level (R = -0.85), a low albumin to fibrinogen ratio (R = -0.89) and a high resistance to lysis (R = -0.82). High triglycerides level was the only plasma modification related to the slower fibrin lysis rate (R = -0.54). High fibrin rigidity (G’) was the only fibrin parameter simultaneously related to the nephrotic state (R = 0.75) and the lysis resistance (R = -0.71). After eliminating the effects of age, albumin and fibrinogen levels, low fibrin porosity (Ks) and low fiber mass-length ratio (μ) were the main features of the nephrotic state. These findings are discussed in relation to both the pathophysiology of thrombotic complications in nephrotic syndrome and their pharmacological prevention.
Molecular Analyses of the Platelet Glycoprotein Ib-IX-V Receptor
Authors: Ware Jerry 
Published: March 2018

IntroducationGlycoprotein receptors within the platelet membrane are essential for initiating platelet adhesion and aggregation on thrombogenic surfaces. As a response to vascular injury these receptors provide platelets with two essential properties i) the ability to bind adhesive substrates exposed at the site of injury (adhesion) and ii) the ability to recruit additional platelets to form a thrombus (aggregation). It is becoming increasingly evident that defined rheological conditions govern the physiological relevance of specific receptor-ligand interactions along with fundamentally distinct molecular mechanisms for individual receptors and their ligands. Among platelet receptors the glycoprotein (GP) Ib-IX-V complex is important because it initiates thrombus formation over a wide range of flow conditions through an initial interaction with the adhesive ligand, von Willebrand factor. The importance of this receptor-ligand interaction is best exemplified by congenital bleeding disorders resulting from the lack of either the receptor or the ligand, the Bernard-Soulier syndrome and von Willebrand disease, respectively. Additionally, the GP Ib component of the GP Ib-IX-V complex contains a binding site for α-thrombin and recent studies have strengthened the concept that the interaction between α-thrombin and GP Ib is of biological relevance. Unquestionably, studies dissecting the GP Ib-IX-V complex are defining essential aspects of normal hemostasis and thrombosis while providing key information on the molecular mechanisms governing the formation of pathologic platelet thrombi. This review will summarize recent advances in our understanding of the synthesis, structure and function of the platelet GP Ib-IX-V complex. Where possible, directions for future studies will be identified with an overall goal of achieving a more complete understanding on the role of the GP Ib-IX-V complex in platelet biology.
Abnormal Expression of Type 1 Plasminogen Activator Inhibitor and Tissue Factor in Severe Preeclampsia
Authors: Gilabert Juan , Grancha Salvador , Yamamoto Koji , Thinnes Terri , España Francisco , Aznar Justo , Loskutoff David , Estellés Amparo 
Published: March 2018

SummaryPreeclampsia is a multisystemic obstetric disease of unknown etiology that is commonly associated with fibrin deposition, occlusive lesions in placental vasculature, and intrauterine fetal growth retardation. We previously reported that type 1 plasminogen activator inhibitor (PAI-1) levels are significantly increased in plasma and placenta from pregnant women with preeclampsia compared to normal pregnant women. In the present report we localize the expression of placental PAI-1 in greater detail and compare it with that of tissue factor (TF), a procoagulant molecule, and vitronectin (Vn), a PAI-1 cofactor. We also examine the expression of two cytokines, tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), in order to begin to define the underlying mechanisms responsible for the elevated levels of PAI-1 and fibrin deposits observed in placenta from preeclampsia. We demonstrate a significant increase in PAI-1, TF and TNFα antigen and PAI-1 and TF mRNA in placentas from preeclamptic patients. PAI-1 mRNA was increased not only in syncytiotrophoblast and infarction areas, but also in fibroblasts and in some endothelial cells of fetal vessels in placentas from preeclamptic patients. However, there was no colocalization between PAI-1, TF, Vn and TNFα in placental villi. The elevated TNFα in the placenta may induce PAI-1 and TF, and thus promote the thrombotic alterations associated with preeclampsia.
Feasibility Study of Catheter-directed Thrombolysis with Recombinant Staphylokinase in Deep Venous Thrombosis
Authors: Heymans Stephane , Verhaeghe Raymond , Stockx Luc , Collen Désiré 
Published: March 2018

SummaryThe feasibility of catheter-directed thrombolysis with recombinant staphylokinase was evaluated in six selected patients with deep vein thrombosis. The patients underwent intrathrombus infusion of recombinant staphylokinase (2 mg bolus followed by a continuous infusion of 1 mg/h). Heparin was given via the catheter as a bolus (5000 U) and as a continuous infusion (1000 U/h). Complete lyis was obtained in five patients and partial lysis in one patient. Complications consisted of minor bleeding in four subjects. Symptomatic reocclusion occurred in one. Debulking of the thrombus mass by a high speed rotating impeller (n = 1) and stenting (n = 3) were used as additional interventions. An underlying anatomical abnormality was present in two patients. Long term follow up revealed normal patency in all patients and normal valve function in four patients. Symptomatic venous insufficiency with valve dysfunction was present in the two with a second thrombotic episode.Thus catheter-directed infusion of recombinant staphylokinase in patients with deep vein thrombosis appears feasible and may be associated with a high frequency of thrombolysis. Larger studies to define the clinical benefit of this treatment appear to be warranted.
Sensitivity, Specificity and Predictive Value of Modified Assays for Activated Protein C Resistance in Children
Authors: Brandt Greg , Glueck Charles , Stroop Davis , Becker Ann , Pillow Ann , Wang Ping , Gruppo Ralph 
Published: March 2018

SummaryVery little data is available assessing the clinical utility of coagulation-based APC resistance assays compared to DNA-based analysis for the factor V Leiden mutation in children. Therefore, the clinical utility of four aPTT-based assays for APC resistance was evaluated in 169 children, ages 3 months through 16 years. The prevalence of the Arg506 to Gln mutation was 7/169 (4.1%). Using cutoff points derived from the normal PCR-screened population (n = 162), two assays for APC resistance (APC-SR and n-APC-SR) gave poor concordance with the PCR assay (sensitivity 29% and 57%, respectively). Two modified assays (FDAPC-SR and n-FDAPC-SR), in which patient plasma was prediluted 1:5 in factor V deficient plasma, gave excellent concordance (sensitivity 100%). The predictive value of a positive test was 0.25, 0.44, 1.00 and 0.88 for the APC-SR, n-APC-SR, FDAPC-SR and n-FDAPC-SR, respectively. The FDAPC-SR and n-FDAPC-SR tests gave excellent discrimination using cutoff values derived from the total population (n = 169) without regard to previous PCR screening results.
Relation of Urokinase-Type Plasminogen Activator Expression to Presence and Severity of Atherosclerotic Lesions in Human Coronary Arteries
Authors: Padró Teresa , Steins Martin , Li Chang-Xun , Schmid Kurt , Hammel Dieter , Scheld Hans , van de Loo Jürgen , Kienast Joachim 
Published: March 2018

SummaryUrokinase-type plasminogen activator (UPA) has been implicated in a broad spectrum of pathological processes – e.g. cell adhesion, migration and proliferation and matrix remodeling – that are considered important features of atherogenesis and plaque disruption. In this study, we have analyzed the content and expression of UPA in human coronary arteries and its relation to the presence and severity of atherosclerotic lesions. Segments of coronary arteries obtained from human heart explants (n = 15) were classified by the presence and types of atherosclerotic lesions. UPA was quantitatively determined in protein extracts of the intimal and medial layers. In situ hybridization and immunohistochemical analyses were performed on serial sections of representative tissue specimens. UPA was detected in the extracts as pro-UPA, UPA complexed to plasminogen activator inhibitor-1, or as otherwise inactive UPA antigen, but not in the active two-chain form. Both functional and total UPA were increased several-fold in extracts of advanced lesions, while the ratios of functional over total UPA showed the opposite trend suggesting enhanced UPA inactivation and turnover. UPA expression in early atherosclerotic lesions was particularly prominent in areas of proliferating SMCs in the abluminal part of the neointima, whereas in advanced lesions UPA was widely expressed in macrophage-rich areas adjacent to the rims and shoulder regions of the necrotic cores. The results strongly suggest a causal involvement of UPA in coronary atherogenesis and its clinical outcome.
Alboaggregins A and B. Structure and Interaction with Human Platelets
Authors: Tan Li , Holt John , Peng Manling , Karczewski Jerzy , Calvete Juan , Kowalska Anna , Niewiarowski Stefan 
Published: March 2018

SummaryViper venoms contain a variety of platelet binding proteins including those which bind to platelet GPIb/GPIX. Most of these proteins inhibit von Willebrand factor mediated platelet agglutination. Here we report the primary structures of unique members of this family, alboaggregins A and B, isolated from Trimeresurus albolabris, which have the ability to stimulate platelet agglutination and aggregation. Four chains of alboaggregin A and two chains of alboaggregin B share a high degree of homology and all cysteines in both alboaggregins are conserved. Both alboaggregins caused similar agglutination of fixed platelets. Alboaggregin A induced platelet aggregation and release reaction with EC50 = 10 and 30 nM, respectively, which is 20-fold lower than those for alboaggregin B. These observations suggest that the dimeric structure of alboaggregin B is sufficient to mediate its binding to GPIb and induce agglutination of platelets whereas aggregation and release reaction are significantly enhanced by tetrameric structure of alboaggregin A.
Prospective, Randomised Trial of Two Doses of rFVIIa (NovoSeven) in Haemophilia Patients with Inhibitors Undergoing Surgery
Authors: Gilchrist Gerald , Hoots W. Keith , Cooper Herbert , Gastineau Dennis , Shapiro Amy 
Published: March 2018

SummaryRecombinant factor VIIa (rFVIIa; NovoSeven® ; Novo Nordisk) has proven efficacy in the treatment of haemophilic patients with inhibitors. This prospective, double-blind study compared rFVIIa (35 vs. 90 μg/kg) in the initiation and maintenance of haemostasis during and after elective surgery. Patients with inhibitors (FVIII, n = 26; FIX, n = 3) received rFVIIa immediately prior to incision; intraoperatively as needed; every 2 h for the first 48 h; and every 2-6 h for the following 3 days. Haemostasis was evaluated during surgery, at 0, 8, 24 and 48 h and 3, 4 and 5 days after wound closure. After day 5, open-label rFVIIa (90 μg/kg) was available for maintenance. Intraoperative haemostasis was achieved in 28/29 patients. All high-dose patients and 12/15 low dose patients had satisfactory haemostasis during the first 48 h. Twenty-three patients (13/14 high dose) successfully completed the study. Although the 35 μg/kg dose is probably sub-optimal for post-operative management, at least in major procedures, rFVIIa 90 μg/kg is an effective first-line option in surgery for patients with inhibitors.
French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance
Authors: Laurian Y. , Satre E. P. , Derlon A. Borel , Chambost H. , Moreau P. , Goudemand J. , Parquet A. , Peynet J. , Vicariot M. , Beurrier P. , Claeyssens S. , Durin A. , Faradji A. , Fressinaud E. , Gaillard S. , Guérin V. , Guérois C. , Pernod G. , Pouzol P. , Schved J. F. , Gazengel C. , Rothschild C. 
Published: March 2018

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.
Topological Studies of the Amino Terminal Modules of Vitamin K-dependent Protein S Using Monoclonal Antibody Epitope Mapping and Molecular Modeling
Authors: Giri Tusar , Villoutreix Bruno , Wallqvist Anders , Dahlbäck Björn , Frutos Pablo García de 
Published: March 2018

SummaryProtein S is an important anticoagulant protein acting as cofactor to activated protein C (APC) in the degradation of membrane-bound factors Va and VIIIa. Binding of protein S to the membrane depends on the Gla-domain, whereas sites for APC-interaction are located in the thrombin-sensitive region (TSR) and the first EGF domain. The aims of the present investigation were to localize the sites on protein S which are involved in APC-cofactor function and to elucidate possible orientations of the TSR in relation to the membrane. For these purposes, we determined the epitope for a calcium-dependent monoclonal antibody (HPS67) against the TSR, which inhibits APC cofactor activity even though it does not impede protein S binding to the membrane. HPS67 did not recognize wild-type mouse protein S but gained reactivity against a recombinant mouse protein in which G49 and R52 were mutated to R and Q (found in human protein S), respectively, suggesting these two residues to be part of a surface exposed epitope for HPS67. This information helped in the validation and refinement of the structural model for the Gla-TSR-EGF1-modules of protein S. The X-ray structure of a Fab-fragment mimicking HPS67 was docked onto the protein S model. The observation that HPS67 did not inhibit phospholipid binding of protein S has implications for the possible orientation of protein S on the membrane surface. In the proposed model for membrane-bound protein S, there is no contact between the TSR and the membrane. Rather, the TSR is free to interact with membrane-bound APC.
Fibrinogen Plasma Levels in an Apparently Healthy General Population – Relation to Environmental and Genetic Determinants
Authors: Cappucci Giuseppe , Colaizzo Donatella , Pirro Leonardo , Vecchione Gennaro , Grandone Elvira , Minno Giovanni Di , Margaglione Maurizio 
Published: March 2018

SummaryElevated fibrinogen levels are an independent risk factor for cardiovascular ischemic disease. We investigated the relationship between cardiovascular ischemic risk factors, the fibrinogen Bβ-chain G/A-455 polymorphism and plasma fibrinogen levels in 989 apparently healthy subjects. Fibrinogen values were higher in subjects with C reactive protein (C-RP) > 0.33 mg/dl, BMI > 23.9 kg/m2, total cholesterol > 4.84 mmol/l, triglycerides >1.02 mmol/l, PAI-1 antigen >12.2 ng/ml, carriers of the A allele, first-degree relative history of coronary artery disease, or consuming >10 cigarettes per day (p <0.01). Men and ethanol drinkers showed lower plasma fibrinogen levels (p <0.01). The multivariate analysis confirmed the independent effect of C-RP, age, BMI, total cholesterol, gender, PAI-1, -455 G/A polymorphism, (p <0.05). BMI, total cholesterol, PAI-1, alcohol and smoking habit raised with the increase of age and differed between sexes. The A-455 allele increasing effect was significant in women, especially in subjects aged <30 years, and in men aged <43 years. These results indicate that environmental factors contributed to a larger extent to fibrinogen variability, whereas the A-455 allele was associated with a steeper increase in younger age quartiles.
Localization and Translocation of MMP-2 during Aggregation of Human Platelets
Authors: Sawicki Grzegorz , Sanders Esmond , Salas Eduardo , Wozniak Mieczyslaw , Rodrigo Jose , Radomski Marek 
Published: March 2018

SummaryWe have previously shown that human platelets express matrix metalloproteinase-2 (MMP-2) and that the release of this enzyme during platelet activation mediates the ADP- and thromboxane-independent part of aggregation. We have now used immunogold electron microscopy, flow cytometry, Western blot analysis and zymography methods to study the ultrastructural localization of MMP-2 in human washed platelets. Platelet aggregation was stimulated by collagen and the MMP-2 immunoreactivity of platelets was followed during various stages of aggregation. In resting platelets, MMP-2 was randomly distributed in the platelet cytosol without detectable association with platelet granules. Platelet aggregation caused the translocation of MMP-2 from the cytosol to the extracellular space. During the early stages of aggregation, MMP-2 remained in close association with the platelet plasma membrane. We conclude that the interactions of MMP-2 with platelet surface membranes mediate the aggregatory response induced by this enzyme.
Vitamin E, Atherosclerosis and Thrombosis
Authors: Micheletta Fausta , Iuliano Luigi , Violi Francesco 
Published: March 2018

SummaryVitamin E, a major lipid-soluble, chain-breaking antioxidant includes several tocopherols having the biological activity of RRR-alpha-tocopherol. Vitamin E circulates in the blood as free tocopherol bound to beta-lipoproteins and is present in cell membrane where it exerts a potent defence against lipid peroxidation (1). Blood concentration of vitamin E in humans ranges from 25 to 30 μM, depending on daily intake and body’s ability to absorb fat (1). In the last decade the scientific interest on biological activity of vitamin E increased because of a growing body of evidence linking this vitamin with atherosclerosis and its complications (2). Thus, the oxidative hypothesis of atherosclerosis suggests that LDL accumulates within vessel wall, in particular in the macrophages, as a consequence of its oxidative modification mediated by resident cells (3, 4). A reduced defence against LDL oxidation could favour this process and accelerate atherosclerotic progression. Accordingly, patients with coronary heart disease have lower plasma concentration of vitamin E than controls (2) and prospective studies demonstrated that a daily assumption of vitamin E reduces cardiovascular events (5). According to the oxidative hypothesis of atherosclerosis, this effect has been attributed to the inhibition of LDL oxidation. Alternative mechanism potentially implicated in the antiatherosclerotic activity of vitamin E includes its interference with the activity of platelet and monocyte, in which the intracellular redox status plays an important functional role (6, 7). As platelets and monocytes are both involved in the pathophysiologic process leading to atherosclerotic lesion, the interference of vitamin E with the biological function of these cells may represent another important tool to explore the anti-atherosclerotic activity of vitamin E. This review will focus on the open issues related to the use of vitamin E in clinical studies and the potential usefulness in investigating platelet function and clotting activation in patients treated with vitamin E.
Plasma Levels of Syndecan-4 (Ryudocan) Are Elevated in Patients with Acute Myocardial Infarction
Authors: Takagi Akira , Maeda Masahiro , Segawa Tatsuya , Shimizu Atsuya , Yamamoto Koji , Matsushita Tadashi , Saito Hidehiko , Kojima Tetsuhito 
Published: March 2018

SummarySyndecan-4 (ryudocan) is a cell-surface heparan sulfate proteoglycan, which plays an important role in a variety of biological functions including regulation of blood coagulation, cell adhesion, and cell growth. In this study, we measured plasma levels of syndecan-4 in patients with acute myocardial infarction using an enzyme-immunoassay, and found that they were extremely high, with a peak of average (10.5 ± 5.6 ng/ml, 2 weeks after onset), as compared with those in normal subjects (0.078 ± 0.030 ng/ml) (p < 0.001). We also observed a distinct expression of syndecan-4 in the repair region of the damaged cardiac tissues with infarction, but not in intact region, by immunohistochemical analysis. To clarify the mechanism of syndecan-4 induction, we investigated the hypoxia effect on its expression, and found that hypoxia treatment up-regulated the gene expression of syndecan-4 in various types of cells. Taken together, it is suggested that syndecan-4 is induced by hypoxia stimuli in ischemic heart tissues, and may function as a tissue-repair molecule via biological mediators such as heparin-binding growth factors.
Antibodies to Phosphatidylethanolamine as the only Antiphospholipid Antibodies Found in Patients with Unexplained Thromboses
Authors: Alessi Marie-Christine , Harle Jean Robert , Sapin Christophe , Aillaud Marie-Françoise , Gentile Stéphanie , Juhan-Vague Irène , Weiller Pierre-Jean , Sanmarco Marielle 
Published: March 2018

SummaryThe objective of this study was to assess the interest of antiphosphatidylethanolamine antibodies (aPE) in unexplained thrombosis (UT) defined as thrombotic episode without any of the main autoimmune and hereditary thrombophilic defects. Results from 98 UT were compared to those of (I) 142 patients with thrombophilia: 67 antiphospholipid syndrome (APS) and 75 hereditary hemostatic defects (HHD); (II) 110 patients without thrombosis: 60 with systemic lupus erythematosus (SLE) and 50 with infectious diseases (ID). As compared to controls (100 blood donors), aPE prevalence was significantly higher in both autoimmune contexts (APS: 43%; SLE: 40%, p <0.0001) and among non-autoimmune pathologies, only in UT (18%, p = 0.001) conversely to HHD (8%) or ID (10%). aPE prevalence in UT was not statistically different from that found in Primary APS (32%, p = 0.076) but lower than in Secondary APS (65%, p <0.005). In UT, aPE were mainly of IgM isotype like in Primary APS and they were found alone whereas in SLE they were always associated with classical anti-phospholipid antibodies. No significant association was found between any isotype of aPE and a site of thrombosis in UT as well as in APS. In conclusion, this study demonstrates an increase of the prevalence of aPE in patients with unexplained thrombosis. Thus, aPE investigation appears to be of interest in UT and their persistent presence could define a biological variant of APS.