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Blood Coagulation (blood + coagulation)
Terms modified by Blood Coagulation Selected AbstractsCommentary on book review: A History of Blood CoagulationHAEMOPHILIA, Issue 1 2002E. G. D. TUDDENHAM No abstract is available for this article. [source] Anticoagulation Options for Pediatric HemodialysisHEMODIALYSIS INTERNATIONAL, Issue 2 2003Andrew Davenport Blood coagulation in the extracorporeal hemodialysis circuit is one of the manifestations of bio-incompatibility that is related to the activation of monocytes, platelets, and the coagulation cascades. Compared to adults, in pediatric patients, the surface area of the extracorporeal circuit is increased relative to blood volume. This is due to the patient's smaller blood volume and the combination of the higher relative surface area of the dialyzer, smaller lumen lines, and small-bore vascular catheters, potentially increasing contact activation of coagulation proteins, platelets, and inflammatory cells. Although unfractionated heparin remains the most commonly used anticoagulant, low molecular weight heparin offers the advantages of a single bolus, less fibrin and platelet deposition in the dialyzer, and perhaps more importantly, less osteoporosis, hyperkalemia, and abnormal lipoprotein profile. Although regional anticoagulants are available, these are often prohibitively expensive or require increased complexity of the dialysis procedure (e.g., citrate), but have the advantage of reducing the risk of bleeding when compared to heparin. Thrombin inhibitors are now available, and with the advent of argatroban, which is metabolized in the liver, have become the anticoagulants of choice for the few patients who develop heparin-induced thrombocytopenia type II. [source] Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseasesJOURNAL OF INTERNAL MEDICINE, Issue 3 2005BJÖRN DAHLBÄCK Abstract. Platelet-mediated primary haemostasis and blood coagulation have evolved as important defence mechanisms against bleeding. The formation of the platelet plug provides the initial occlusion of the vascular lesion. This is temporally co-ordinated with the activation of the coagulation system, which occurs in response to the rupture of endothelium and the exposure of blood to the extravascular tissue. The reactions of blood coagulation are carefully controlled by several anticoagulant mechanisms and under normal conditions they prevail over the procoagulant forces. Genetic or acquired disturbances of the natural balance between the pro- and anticoagulant systems may result in bleeding or thrombotic diseases. [source] Development of an inhibitory antibody fragment to human tissue factor using phage display technologyDRUG DEVELOPMENT RESEARCH, Issue 3 2009S.M. Meiring Abstract Tissue factor is involved in the etiology of thrombotic diseases initiating the thrombosis associated with the inflammation that occurs during infection. The prevention of blood coagulation and inflammation is of primary importance in a number of pathological situations. A single-chain variable antibody fragment of molecular weight of 26,kD that inhibits the action of human tissue factor was selected by phage display technology, purified and tested for its tissue factor inhibitory effect, purified on a protein A column, and its purity evaluated on SDS-PAGE. The effects of the antibody fragment on prothrombin times, Factor Xa production, and thrombin generation were assessed with increasing fragment concentrations, using chromogenic and fluorometric substrates. The antibody fragment dose-dependently prolonged the prothrombin time (IC50=0.5,,M) and delayed the lag phase before the thrombin generation burst and the peak thrombin concentration in the thrombin generation assay. The effect on thrombin generation was more pronounced in thrombophilic plasma than in normal plasma. Antibody-based tissue factor inhibitors therefore may provide an effective treatment for thrombotic disease without serious bleeding complications. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc. [source] Activation loop 3 and the 170 loop interact in the active conformation of coagulation factor VIIaFEBS JOURNAL, Issue 11 2009Egon Persson The initiation of blood coagulation involves tissue factor (TF)-induced allosteric activation of factor VIIa (FVIIa), which circulates in a zymogen-like state. In addition, the (most) active conformation of FVIIa presumably relies on a number of intramolecular interactions. We have characterized the role of Gly372(223) in FVIIa, which is the sole residue in activation loop 3 that is capable of forming backbone hydrogen bonds with the unusually long 170 loop and with activation loop 2, by studying the effects of replacement with Ala [G372(223)A]. G372A-FVIIa, both in the free and TF-bound form, exhibited reduced cleavage of factor X (FX) and of peptidyl substrates, and had increased Km values compared with wild-type FVIIa. Inhibition of G372A-FVIIa·sTF by p -aminobenzamidine was characterized by a seven-fold higher Ki than obtained with FVIIa·sTF. Crystallographic and modelling data suggest that the most active conformation of FVIIa depends on the backbone hydrogen bond between Gly372(223) and Arg315(170C) in the 170 loop. Despite the reduced activity and inhibitor susceptibility, native and active site-inhibited G372A-FVIIa bound sTF with the same affinity as the corresponding forms of FVIIa, and burial of the N-terminus of the protease domain increased similarly upon sTF binding to G372A-FVIIa and FVIIa. Thus Gly372(223) in FVIIa appears to play a critical role in maturation of the S1 pocket and adjacent subsites, but does not appear to be of importance for TF binding and the ensuing allostery. [source] Milder clinical presentation of haemophilia A with severe deficiency of factor VIII as measured by one-stage assayHAEMOPHILIA, Issue 1 2001K. Ghosh During the course of investigations we encountered 11 patients with haemophilia A who had severe factor VIII deficiency as measured by one-stage assay but had surprisingly mild clinical presentation. Four of these patients had either a brother, nephew or maternal uncle with severe clinical manifestations. Two patients had low protein S levels, and one was heterozygous for the factor V Leiden mutation. One patient had a combined deficiency of protein C and antithrombin III. Four patients had a two-stage factor VIII assay value that was much higher than the one-stage assay value. Five patients were heterozygous for the MTHFR gene C677T polymorphism, of whom two patients were also deficient for protein S and one had two-stage factor assay values higher than the one-stage assay values. The patient who was both factor VIII deficient and heterozygous for factor V Leiden had mild clinical presentation as compared to his maternal uncle who was only factor-VIII deficient. The maternal cousin of the same patient was heterozygous for factor V Leiden and had suffered two thrombotic episodes. Thus, the present study advocates that the physiological inhibitors of blood coagulation also play an important role in cases of haemophilia A in the final outcome of haemostasis in vivo. [source] Factor XI deficiency and its managementHAEMOPHILIA, Issue 2000Bolton-Maggs Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype. Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups. Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study. [source] Mechanism of blood coagulation in common carp (Cyprinus carpio)INTEGRATIVE ZOOLOGY (ELECTRONIC), Issue 3 2006Shuangan LI Abstract In vitro, carp blood was anticoagulated by using MgSO4 at a final concentration of 22.2 mmol L,1 and sodium citrate at a final concentration of 11.8 mmol L,1. The coagulation times for carp plasma diluted by ion-free water (1:1), and that of carp plasma to which thrombocytes and small lymphocytes were added, were measured at 23 °C using standard methods, and then contrasted with the coagulation times for plasma obtained from chickens and rabbits. The shapes of the thrombocytes and small lymphocytes, which were either wet mounted or stained with hematoxylin and eosin, were observed under a light microscope. We found that: (i) the coagulation reaction of carp blood was significantly (P < 0.01) accelerated by the addition of ion-free water; (ii) the three types of blood cells (thrombocytes, small lymphocytes and red blood cells) promoted plasma coagulation to a similar extent (P > 0.05); (iii) in carp Mg2+ plasma and K2C2O4 plasma, the thrombocytes were usually morphologically normal, but many small lymphocytes were destroyed and became aggregated; (iv) in the citrate plasma, thrombocytes were often aggregated, but the small lymphocytes were usually morphologically normal; and (v) the coagulation time for chicken and rabbit plasma was significantly extended by adding ion-free water. [source] CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Cam V. Ngo Abstract Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. © 2006 Wiley-Liss, Inc. [source] Identification of a novel human tissue factor splice variant that is upregulated in tumor cells,INTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Hitendra S. Chand Abstract Tissue factor (TF) is a transmembrane glycoprotein that serves as the prime initiator of blood coagulation and plays a critical role in thrombosis and hemostasis. In addition, a variety of tumor cells overexpress cell-surface TF, which appears to be important for tumor angiogenesis and metastasis. To elucidate the mechanism involved in the upregulation of TF in human tumor cells, a comprehensive analysis of TF mRNA from various normal and tumor cells was performed. The results of these studies indicate that, in addition to possessing a normal full-length TF transcript and minor levels of an alternatively spliced transcript known as alternatively-spliced tissue factor (asTF) (Bogdanov et al., Nat Med 2003;9:458,62), human tumor cells express additional full-length TF transcripts that are also generated by alternative splicing. Reverse transcriptase-polymerase chain reaction (RT-PCR) and 5,-rapid amplification of cDNA ends- (5,-RACE) based analyses of cytoplasmic RNA from normal and tumor cells revealed that there is alternative splicing of the first intron between exon I and exon II resulting in 2 additional TF transcripts. One of the transcripts has an extended exon I with inclusion of most of the first TF intron (955 bp), while the second transcript is formed by the insertion of a 495 bp sequence, referred to as exon IA, derived from an internal sequence of the first intron. The full length TF transcript with alternatively spliced novel exon IA, referred to as alternative exon 1A-tissue factor (TF-A), represented ,1% of the total TF transcripts in normal cells, but constituted 7,10% of the total TF transcript in tumor cells. Quantitative real-time RT-PCR analysis indicated that cultured human tumor cells contain 10,25-fold more copy numbers of TF-A in comparison to normal, untransformed cells. We propose that high-level expression of the novel TF-A transcript, preferentially in tumor cells, may have utility in the diagnosis and staging of a variety of solid tumors. © 2005 Wiley-Liss, Inc. [source] Bleeding complications: therapeutic strategies in haemostasisISBT SCIENCE SERIES: THE INTERNATIONAL JOURNAL OF INTRACELLULAR TRANSPORT, Issue n1 2010M. Spannagl Several haemostyptic agents as well as cellular and plasmatic blood products are available for treatment of bleeding complications. Selective application of these compounds according to the patient's haemostatic disturbances is superior to standard application of cellular concentrates and fresh frozen plasma. Near-patient testing of whole blood coagulation and fibrinolysis has been suggested for goal directed therapy. Recent data show reduction of consumption of blood products using algorithms and tailored therapy. [source] Protease-Activated Receptors: A Means of Converting Extracellular Proteolysis into Intracellular SignalsIUBMB LIFE, Issue 6 2002E. J. Mackie Abstract Protease-activated receptors (PARs) mediate cellular responses to a variety of extracellular proteases. The four known PARs constitute a subgroup of the family of seven-transmembrane domain G protein-coupled receptors and activate intracellular signalling pathways typical for this family of receptors. Activation of PARs involves proteolytic cleavage of the extracellular domain, resulting in formation of a new N terminus, which acts as a tethered ligand. PAR-1, -3, and -4 are relatively selective for activation by thrombin whereas PAR-2 is activated by a variety of proteases, including trypsin and tryptase. Recent studies in mice genetically incapable of expressing specific PARs have defined roles for PAR-1 in vascular development, and for PAR-3 and -4 in platelet activation, which plays a fundamental role in blood coagulation. PAR-1 has also been implicated in a variety of other biological processes including inflammation, and brain and muscle development. Responses mediated by PAR-2 include contraction of intestinal smooth muscle, epithelium-dependent smooth muscle relaxation in the airways and vasculature, and potentiation of inflammatory responses. The area of PAR research is rapidly expanding our understanding of how cells communicate and control biological functions, in turn increasing our knowledge of disease processes and providing potential targets for therapeutic intervention. [source] Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseasesJOURNAL OF INTERNAL MEDICINE, Issue 3 2005BJÖRN DAHLBÄCK Abstract. Platelet-mediated primary haemostasis and blood coagulation have evolved as important defence mechanisms against bleeding. The formation of the platelet plug provides the initial occlusion of the vascular lesion. This is temporally co-ordinated with the activation of the coagulation system, which occurs in response to the rupture of endothelium and the exposure of blood to the extravascular tissue. The reactions of blood coagulation are carefully controlled by several anticoagulant mechanisms and under normal conditions they prevail over the procoagulant forces. Genetic or acquired disturbances of the natural balance between the pro- and anticoagulant systems may result in bleeding or thrombotic diseases. [source] Hormone replacement therapy and cardiovascular disease: increased risks of venous thromboembolism and stroke, and no protection from coronary heart diseaseJOURNAL OF INTERNAL MEDICINE, Issue 5 2004G. D. O. Lowe Abstract. Hormone replacement therapy (HRT) was increasingly promoted over the last 40 years to improve quality of life, and to reduce the risks of osteoporotic fractures and coronary heart disease (CHD). In recent years, observational studies, randomized trials and systematic reviews of such trials have shown that HRT does not reduce, but actually increases cardiovascular risk. HRT increases the relative risks of venous thromboembolism (twofold), and of fatal or disabling stroke (by 50%); whilst increasing the early risk of myocardial infarction and having no protective effect against CHD on longer term use. Possible mechanisms for these increased cardiovascular risks include down-regulation of several inhibitory pathways of blood coagulation, resulting in increased coagulation activation, which promotes venous and arterial thrombosis. The implications for prescription are discussed, as are lessons for future evaluation of health care interventions. [source] Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy,JOURNAL OF MEDICAL VIROLOGY, Issue 5 2006J. Ren Abstract Hepatitis B virus (HBV)-associated nephritis has been reported worldwide. Immune complex deposition has been accepted as its pathogenesis, although the association between the presence of local HBV DNA and viral antigen and the development of nephritis remains controversial. To understand better the roles played by HBV protein expression in the kidney, the global gene expression profile was studied in the kidney tissue of a lineage of HBV transgenic mouse (#59). The mice expressed HBsAg in serum, and HBsAg and HBcAg in liver and kidney, but without virus replication. Full-length HBV genome (adr subtype, C genotype) isolated from a chronic HBV carrier was used to establish the transgenic mice #59. Similarly manipulated mice that did not express HBV viral antigens served as controls. Southern blotting, hybridization with HBV probe, and immuno-histochemical staining were used to study HBV gene expression. mRNA extracted from the kidney tissue was analyzed using Affymetrix microarrays. HBsAg and HBcAg were located mainly in the cytoplasm of tubular epithelium. Altogether 520 genes were "up-regulated" more than twofold and 76 genes "down-regulated" more than twofold in the kidney. The complement activation, blood coagulation, and acute-phase response genes were markedly "up-regulated". Compared to the controls, the level of serum C3 protein was decreased in #59 mice, while the level of C3 protein from kidney extract was increased. Results indicate that expression of HBsAg and HBcAg in tubular epithelial cells of the kidney per se can up-regulate complement-mediated inflammatory gene pathways, in addition to immune complex formation. J. Med. Virol. 78:551,560, 2006. © 2006 Wiley-Liss, Inc. [source] Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2003Takaaki Yasuda ABSTRACT Shimotsu-To, which consists of four herbal extracts, has been used clinically for improving abnormal blood coagulation, fibrinolysis, atherosclerosis and chronic inflammation in Japan and China. We have investigated the pharmacological relationship between the effects and chemical components of Shimotsu-To after oral administration to rats. The urinary constituents were separated and identified by three dimensional (3D-) HPLC equipped with a photodiode array detector as a new tool and the chemical structures were determined by spectroscopic methods to be trans -ferulic acid-3- O -sulfate (1), vanillic acid (2), m -hydroxyphenylpropionic acid (3), trans -ferulic acid (4) and cis -ferulic acid (5). Of these compounds, 2,5 strongly inhibited platelet aggregation induced by ADP and arachidonic acid. Compound 1, the sulfate conjugate of 4, did not show any inhibitory effect, which suggested that the inhibitory effect on platelet aggregation was inactivated by sulfate conjugation. These results indicated that compounds 2,5 partly contributed to the anti-Oketsu effect of Shimotsu-To through the inhibition of platelet aggregation. [source] Air pollution and hospitalization for venous thromboembolic disease in ChileJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2010R. E. DALES See also Mannucci PM. Fine particulate: it matters. This issue, pp 659,61; Bonzini M, Tripodi A, Artoni A, Tarantini L, Marinelli B, Bertazzi PA, Apostoli P, Baccarelli A. Effects of inhalable particulate matter on blood coagulation. This issue, pp 662,8. Summary.,Background:,Ambient air pollution is a risk factor for stroke and myocardial infarction, possibly because of alterations in coagulation that influence the arterial circulation. Whether air pollution influences diseases associated with peripheral venous thrombogenesis remains largely unknown. Objectives: To determine the association between air pollution and venous thromboembolic disease (VTE) in a sample of the general population. Methods: A time-series analysis was used to test the association between daily air pollution and VTE hospitalizations in Santiago between 2001 and 2005. Results were adjusted for long-term trends, day of the week and average daily humidex. Results: From a population of 5.4 million, there were, on average, 2.3 admissions for VTE per day. Pooled estimates of relative risk (RR) [95% confidence interval (CI)] of hospitalization for venous disease were: 1.07 (1.05, 1.09) for a 58.4 p.p.b. increase in ozone (O3); 1.06 (1.02, 1.09) for a 5.85 p.p.b. increase in sulphur dioxide (SO2); 1.08 (1.03, 1.12) for a 29.25 ,g/m3 increase in nitrogen dioxide (NO2); and 1.05 (1.03, 1.06) for a 20.02 ,g/m3 increase in particulate matter , 2.5 ,m in mean aerodynamic diameter (PM2.5). For pulmonary embolism (PE) results were: 1.10 (1.07, 1.13) for O3; 1.05 (1.02, 1.08) for SO2; 1.07 (1.04, 1.09) for NO2; and 1.05(1.03, 1.06) for PM2.5, respectively. Conclusion: Air pollution appears to be a risk factor for venous thrombosis and PE, a disease with a significant fatality rate. [source] Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adultsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2008L. A. LANGE Summary.,Background and Objectives:,D-dimer is a hemostasis marker that reflects ongoing fibrin formation and degradation. There is significant inter-individual and inter-population variability in D-dimer concentration, but whether genetic factors underlie these differences is largely unknown. We hypothesized that common coagulation gene variants contribute to differences in circulating D-dimer concentration. Methods:,The setting was European-American (EA; n = 1858) and African-American (AA; n = 327) unrelated older adults from the Cardiovascular Health Study (CHS), in which we genotyped SNPs in 42 genes related to blood coagulation and fibrinolysis. Results:,Several fibrinogen gene polymorphisms, including the Thr312Ala A, chain variant and the FGG-10034 C/T variant, were associated with ,20% higher plasma D-dimer levels in EA (false discovery rate < 5% for covariate-adjusted model). There was also some evidence that a Pro41Leu variant of the PLAU gene encoding urinary plasminogen activator and non-coding polymorphism of the plasminogen activator inhibitor type 1 gene (SERPINE1) were associated with higher plasma D-dimer in EA. There were no significant associations between the studied coagulation or fibrinolysis gene SNPs and plasma D-dimer levels in the smaller AA sample. However, each standard deviation increase in European ancestry assessed by ancestry-informative gene markers was associated with ,10% lower mean D-dimer levels in AA. Conclusions:,Together, common coagulation/fibrinolysis gene SNPs explained only ,2% of the variance in plasma D-dimer levels in EA. These findings suggest that the association of D-dimer with risk of vascular outcomes may be mediated largely by environmental factors, other genes, and/or genetic interactions. [source] Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2008L. A. SNYDER Summary.,Background:,Tissue factor (TF) is expressed widely at the subluminal surface of blood vessels and serves as the primary cellular initiator of the extrinsic pathway of blood coagulation. Lack of TF in mice resulted in lethality in utero, but human TF (huTF) expressed at low levels from a human minigene rescued null mice from prenatal death. Although these low-TF expressing transgenic mice developed to term, they had a significantly shorter life span and exhibited hemorrhage and fibrosis in the heart. Methods:,Human TF knock-in (TFKI) mice were generated by replacing the first two exons of the mouse (murine) TF (muTF) gene with the huTF complete coding sequence, thus placing it under the control of the endogenous muTF promoter. Results:,Expression of huTF in the TFKI mice was similar to muTF in wild-type (wt) mice. The TFKI mice showed no microscopic evidence of spontaneous hemorrhage in the heart, nor cardiac fibrosis at up to 18 months of age. Immunohistochemistry showed that huTF was expressed in cells surrounding blood vessels in TFKI mice. Coagulation activity of brain homogenates from TFKI mice was comparable with that from wt brain. Cardiac hemorrhage similar to that of the low-TF transgenic mice occurred in the TFKI mice when huTF was blocked by a neutralizing anti-huTF monoclonal antibody. Conclusion:,We generated a transgenic mouse line that expresses huTF under the control of the endogenous muTF promoter at physiological levels. Our results suggest that huTF can fully reconstitute the murine coagulation system and mediate normal hemostasis. [source] Tissue factor-dependent blood coagulation is enhanced following delivery irrespective of the mode of deliveryJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2007K. BOER Summary. Background:,The risk of thrombosis is clearly increased in the postpartum period. Mice with a targeted deletion of the transmembrane domain of tissue factor (TF) develop serious activation of blood coagulation and widespread thrombosis after delivery. Objective and methods:,We hypothesized that TF, abundantly present in placental tissue, is released during delivery, resulting in the activation of blood coagulation. We measured sensitive markers for TF-dependent activation of coagulation before and after induction of labor in two groups: a vaginal delivery (VAG) group and a cesarean section (CS) group.Results:,One hour after delivery, soluble TF (sTF) significantly increased in both groups [VAG group (mean ± SD) 226 ± 42 to 380 ± 42 pg mL,1 and CS group 193 ± 17 to 355 ± 44 pg mL,1]. The day after delivery, sTF was somewhat less increased. Both groups also showed an increase in factor VIIa, indicating activation of the TF pathway of coagulation. Indeed, after delivery, TF-dependent coagulation, as measured by the TF clotting time assay, was significantly enhanced. Increased plasma levels of prothrombin fragment 1 + 2 and thrombin,antithrombin complexes demonstrated thrombin generation following delivery. TF pathway-dependent activation of coagulation upon delivery was not blocked by TF pathway inhibitor and was not dependent on the mode of delivery.Conclusion:,The postdelivery increase in TF-dependent activation of coagulation is likely to be a natural mechanism to prevent excessive blood loss during and after delivery, and may also indicate a novel mechanism by which puerperal women have an increased risk of venous thromboembolism. [source] Plasmodium falciparum- infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2007I. M. B. FRANCISCHETTI Summary.,Background:,Plasmodium falciparum malaria infects 300,500 million people every year, causing 1,2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria. Objectives:,We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated. Results:,We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum -infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC. Conclusions:,These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications. [source] Mathematical and biological models of blood coagulation.JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2006A rebuttal [source] Real-Time quantitative PCR analysis of factor XI mRNA variants in human plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2004A. Podmore Summary., Coagulation factor XI (FXI) plays an essential role in blood coagulation. A deficiency of FXI is an unusual hemorrhagic diathesis in that the bleeding tendency can be highly variable, ranging from severe deficiencies with no symptoms to mild and moderate deficiencies requiring multiple blood transfusions for hemorrhages. This variability in bleeding has been attributed to a number of factors including the presence of a novel form of FXI associated with platelets, which ameliorates the bleeding in some cases of FXI deficiency. However, the nature of this platelet FXI molecule is controversial. Hsu et al. (J Biol Chem 1998; 273: 13787,93) suggest that it is a product of normal FXI , but lacking exon V whilst Martincic et al. (Blood 1999; 94: 3397,404) were unable to detect this alternatively spliced variant using RT-PCR. In order to resolve this controversy, we have employed the highly sensitive technique of real-time quantitative RT-PCR using RNA isolated from FXI-deficient patients. Our results indicate that the platelets of both normal and FXI deficient individuals contain FXI mRNA that is identical to the mRNA found in liver. An exon V deleted splice variant was not detected. Thus the FXI message is not alternatively spliced in platelets and therefore would not be able to produce an unusual FXI protein. [source] Superantigens from Staphylococcus aureus induce procoagulant activity and monocyte tissue factor expression in whole blood and mononuclear cells via IL-1,JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003E. Mattsson Summary.,Background:,Staphylococcus aureus is one of the most common bacteria in human sepsis, a condition in which the activation of blood coagulation plays a critical pathophysiological role. During severe sepsis and septic shock microthrombi and multiorgan dysfunction are observed as a result of bacterial interference with the host defense and coagulation systems. Objectives:,In the present study, staphylococcal superantigens were tested for their ability to induce procoagulant activity and tissue factor (TF) expression in human whole blood and in peripheral blood mononuclear cells. Methods and results:,Determination of clotting time showed that enterotoxin A, B and toxic shock syndrome toxin 1 from S. aureus induce procoagulant activity in whole blood and in mononuclear cells. The procoagulant activity was dependent on the expression of TF in monocytes since antibodies to TF inhibited the effect of the toxins and TF was detected on the surface of monocytes by flow cytometry. In the supernatants from staphylococcal toxin-stimulated mononuclear cells, interleukin (IL)-1, was detected by ELISA. Furthermore, the increased procoagulant activity and TF expression in monocytes induced by the staphylococcal toxins were inhibited in the presence of IL-1 receptor antagonist, a natural inhibitor of IL-1,. Conclusions:,The present study shows that superantigens from S. aureus activate the extrinsic coagulation pathway by inducing expression of TF in monocytes, and that the expression is mainly triggered by superantigen-induced IL-1, release. [source] Functional characterization of transcription factor binding sites for HNF1-alpha, HNF3-beta (FOXA2), HNF4-alpha, Sp1 and Sp3 in the human prothrombin gene enhancerJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2003H. Ceelie Summary.,Background:,Prothrombin is a key component in blood coagulation. Overexpression of prothrombin leads to an increased risk of venous thrombosis. Therefore, the study of the transcriptional regulation of the prothrombin gene may help to identify mechanisms of overexpression. Objectives:,The aim of our study was to localize the regions within the prothrombin enhancer responsible for its activity, to identify the proteins binding to these regions, and to establish their functional importance. Methods:,We constructed a set of prothrombin promoter 5, deletion constructs containing the firefly luciferase reporter gene, which were transiently transfected in HepG2, HuH7 and HeLa cells. Putative transcription factor (TF) binding sites were evaluated by electrophoretic mobility shift assays. The functional importance of each TF binding site was evaluated by site directed mutagenesis and transient transfection of the mutant constructs. Results:,We confirmed the major contribution of the enhancer region to the transcriptional activity of the prothrombin promoter. Analysis of this region revealed putative binding sites for hepatocyte nuclear factor HNF4, HNF3-beta and specificity protein(Sp)1. We identified six different TFs binding to three evolutionary conserved sites in the enhancer: HNF4-alpha (site 1), HNF1-alpha, HNF3-beta and an as yet unidentified TF (site 2) and the ubiquitously expressed TFs Sp1 and Sp3 (site 3). Mutagenesis studies showed that loss of binding of HNF3-beta resulted in a considerable decrease of enhancer activity, whereas loss of HNF4-alpha or Sp1/Sp3 resulted in milder reductions. Conclusions:,The prothrombin enhancer plays a major role in regulation of prothrombin expression. Six different TFs are able to bind to this region. At least three of these TFs, HNF4-alpha, HNF3-beta and Sp1/Sp3, are important in regulation of prothrombin expression. [source] The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif,the C-domainJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2003R. Al Dieri Summary.,Background:,Heparins in clinical use differ considerably as to mode of preparation, molecular weight distribution and pharmacodynamic properties. Objectives:,Find a common basis for their anticoagulant action. Methods:,In 50 fractions of virtually single molecular weight (Mr), prepared from unfractionated heparin (UFH) and four low-molecular-weight heparins (LMWH), we determined: (i) the molar concentration of material (HAM) containing the antithrombin binding pentasaccharide (A-domain); (ii) the specific catalytic activity in thrombin and factor Xa inactivation; (iii) the capacity to inhibit thrombin generation (TG) and prolong the activated partial thromboplastin time (APTT). We also calculated the molar concentration of A-domain with 12 sugar units at its non-reducing end, i.e. the structure that carries antithrombin activity (C-domain). Results:,The antithrombin activity and the effects on TG and APTT are primarily determined by the concentration of C-domain and independent of the source material (UFH or LMWH) or Mr. High Mr fractions (>15 000) are less active, probably through interaction with non-antithrombin plasma proteins. Anti-factor Xa activity is proportional to the concentration of A-domain, it is Ca2+ - and Mr-dependent and does not determine the effect on TG and APTT. Conclusion:,For any type of heparin, the capacity to inhibit the coagulation process in plasma is primarily determined by the concentration of C-domain, i.e. the AT-binding pentasaccharide with 12 or more sugar units at its non-reducing end. [source] Increasing the efficiency of photodynamic therapy by improved light delivery and oxygen supply using an anticoagulant in a solid tumor modelLASERS IN SURGERY AND MEDICINE, Issue 7 2010Liyong Yang MS Abstract Background and Objective The main factors in photodynamic therapy (PDT) are: photosensitizer retention, photon absorption, and oxygen supply. Each factor has its unique set of problems that poses limitation to the treatment. Both light delivery and oxygen supply are significant bottlenecks in PDT. Vascular closure during PDT reduces oxygen supply to the targeted tissue. On the other hand, with the changes in blood perfusion, the tissue optical properties change, and result in variation in irradiation light transmission. For these reasons, it becomes very important to avoid blood coagulation and vascular closure during PDT. Study Design/Materials and Methods The efficiency of PDT combined with the anticoagulant heparin was studied in a BALB/c mouse model with subcutaneous EMT6 mammary carcinomas. Mice were randomized into three groups: control, PDT-only, and PDT with heparin. The photosensitizer Photofrin® was used in our experiments. Light transmission, blood perfusion, and local production of reactive oxygen species (ROS) were monitored during the treatment. The corresponding histological examinations were performed to determine the thrombosis immediately after irradiation and to evaluate tumor necrosis 48,hours after the treatment. Results The results clearly demonstrated that PDT combined with pre-administered heparin can significantly reduce thrombosis during light irradiation. The blood perfusion, oxygen supply, and light delivery are all improved. Improved tumor responses in the combined therapy, as shown with the histological examination and tumor growth assay, are clearly demonstrated and related to an increased local ROS production. Conclusion Transitory anticoagulation treatment significantly enhances the antitumor effect of PDT. It is mainly due to the improvement of the light delivery and oxygen supply in tumor, and ultimately the amount of ROS produced during PDT. Lasers Surg. Med. 42:671,679, 2010. © 2010 Wiley-Liss, Inc. [source] Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticariaALLERGY, Issue 5 2010S. Takahagi To cite this article: Takahagi S, Mihara S, Iwamoto K, Morioke S, Okabe T, Kameyoshi Y, Hide M. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 2010; 65: 649,656. Abstract Background:, The evaluation of disease severity and activity of chronic urticaria (CU) is essential for the adequate treatment of patients. However, there is no reliable biomarker for such evaluations. Recently, markers of blood coagulation and fibrinolysis have been revealed to be elevated in severe cases of CU. In this article, we studied the coagulation/fibrinolysis and inflammation markers and their relationship to disease activity in patients with CU. Methods:, Plasma fibrin degradation products (FDP), d- dimer and serum C-reactive protein (CRP) were measured with the assessment of disease severity and skin reaction to autologous serum in 82 patients with CU and 37 patients with acute urticaria, idiopathic angioedema (AE) or inducible types of urticaria (IU). Results:, The levels of FDP in patients with CU were significantly higher than those in patients with IU, but no other differences in FDP, d- dimer and CRP were observed among patients with different types of urticaria. These markers of patients with CU were well correlated with each other and significantly associated with disease severity of CU, but not with skin reactions to autologous serum. In 37 patients with CU, levels of all these parameters reduced as their disease condition improved, while they increased when the disease became aggravated. Regarding FDP, this relationship was observed even if FDP concentrations were within normal range throughout the study. Conclusions:, The measurement of plasma FDP, d- dimer and serum CRP may be useful for the assessment of disease activity of CU. [source] Progress in the design of low molecular weight thrombin inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 1 2005Stuti Srivastava Abstract Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed. © 2004 Wiley Periodicals, Inc. [source] GAG Mimetic Libraries: Sulphated Peptide as Heparin-like Glycosaminoglycan Mimics in Their Interaction with FGF-1MOLECULAR INFORMATICS, Issue 8 2005Socorro Vázquez-Campos Abstract Heparin and heparan sulphate (HS) are heterogenous, linear, polysulphated polysaccharides that are important in the regulation of a wide variety of biological processes including blood coagulation, in cell differentiation, adhesion, invasion, migration and development, and in tumor-related cellular events such as growth regulation and metastasis. In general, heparin/HS interacts with proteins mainly through ionic interactions between its negatively charged groups and positively charged groups on the proteins. From a mechanistic or therapeutic standpoint, it is attractive to design less complex charged molecules, other than oligosaccharides, as mimics of heparin. In an attempt to improve the accessibility of heparin mimics, it was assumed, provided that the correct charge topography could be achieved, that sulphated peptides might also act as mimics. Therefore, sulphated peptide combinatorial libraries were generated on solid support to identify novel polyanionic structures that mimic the role of heparin/HS in its binding to fibroblast growth factors (FGFs). Libraries were synthesised by direct sulphation of the peptide on solid phase or by using O- sulphonated building blocks during peptide synthesis. Quantitative solid-phase O -sulphonation of hydroxy amino acid residues in a peptide chain was effected by sulphur trioxide pyridine (SO3 -Pyr) complex in anhydrous pyridine at 65,°C for 4,h. O- Sulphonated building blocks were successfully synthesised in solution and, after stabilisation of the sulphate group by complexion with tetrabutyl ammonium ions, were employed in the synthesis of sulphated peptide libraries, similar to those generated by direct O- sulphonation on solid supports. The libraries were incubated with fluorescent-labelled FGF-1, and analysis and sequence determination of active compounds was carried out using Edman degradation. Selected sulphated peptides from the screening were resynthesised and their affinity for FGF-1 (acidic FGF) was studied in solution competition assays using surface plasmon resonance. These studies showed that sulphated decapeptides do bind to FGF-1 and inhibit its binding to immobilised heparin in the low micromolar concentration range. 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