bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma
Authors: Kuyvenhoven Johan , van Hoek Bart , Blom Eric , van Duijn Wim , Hanemaaijer Roeland , Verheijen Jan , Lamers Cornelis , Verspaget Hein 
Published: March 2018

SummaryMatrix metalloproteinases (MMPs) have the ability to degrade basement membranes and may thus play an important role in extracellular matrix turnover in liver fibrosis and carcinogene-sis. Serum levels of MMPs have been suggested as diagnostic markers in these processes.We measured serum MMP-2 and MMP-9 by ELISA in 91 patients with chronic liver disease, including 25 patients with hepatocellular carcinoma (HCC), and in 60 controls.MMP-2 was significantly higher in patients with chronic liver disease compared to controls, and increased with Child-Pugh class. There was a significant correlation between MMP-2 and liver function (bilirubin, albumin, and prothrombin time), and a strong opposite correlation between MMP-9 and these parameters.MMP-2 levels in patients with HCC were significantly higher than in controls, but comparable to patients with chronic liver disease without this malignancy. MMP-9 yielded no significant differences between patients with or without HCC and controls.Serum MMP-2 and to a lesser extent MMP-9 correlate with the severity of liver disease and may reflect changes in extracellular matrix remodeling. Due to a considerable overlap in patients with chronic liver disease with or without HCC, MMP-2 and MMP-9 can not be used as a diagnostic marker for HCC.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.
Systemic coagulation reactivation in recurrence of colorectal cancer
Authors: Thorlacius-Ussing Ole , Iversen Lene 
Published: March 2018

SummaryAt time of diagnosis, most cancer patients present with laboratory evidence of systemic coagulation activation. After treatment with curative intent, these hemostatic alterations seemingly disappear as seen in colorectal cancer with regard to prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and soluble fibrin (SF).The aim of this study was to investigate whether coagulation activation recurs with cancer recurrence and to study whether preoperative coagulation tests have any prognostic value in colorectal cancer.Plasma F1+2, TAT, and SF levels were prospectively recorded from 113 patients followed after curative resection of colo-rectal cancer. The patients were seen in clinic after 3, 6, 12, and 18 months, and after 2, 3, 4, and 5 years.Coagulation reactivation was observed at the time of recurrence, as demonstrated by significantly increased plasma TAT and SF, along with a non-significant increase (P = 0.09) in F1+2.Preoperative values of F1+2,TAT, and SF did not show association with prognosis.
Tissue factor pathway inhibitor deficiency enhances neointimal proliferation and formation in a murine model of vascular remodelling
Authors: Singh Ripudamanjit , Pan Shuchong , Mueske Cheryl , Witt Tyra , Kleppe Laurel , Peterson Timothy , Caplice Noel , Simari Robert 
Published: March 2018

SummaryTissue factor (TF) is a small-molecular-weight glycoprotein that initiates the extrinsic coagulation pathway but may have important noncoagulation vascular functions as well. Tissue factor pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. Enhancement of vascular TFPI either by overexpression using gene transfer or delivery of protein to the vessel has been shown to reduce neointimal formation. However, the inherent role of TFPI in this process has not been defined. To do so, we utilized a murine model of vascular remodeling using flow cessation in mice, which are heterozygous for a genetic deletion of the first Kunitz domain of TFPI or wild type littermates. The heterozygotic mice had 50% of wild type TFPI activity in plasma as well as vascular homogenates. To study the effect of TFPI deficiency on neointimal formation, age matched TFPIK1+/- and wildtype littermates underwent unilateral common carotid artery ligation. Mice were sacrificed at 4 weeks and the ligated carotid arteries were analyzed. There was a significantly greater neointima to media ratio and less luminal area in the TFPIK1+/- mice compared to their TFPIK1+/+ littermates. The proliferative index of intimal cells in TFPIK1+/-mice at 1 week was significantly higher compared to TFPIK1+/+mice. We conclude that TFPI deficiency enhances neointimal formation and proliferation associated with flow cessation. This suggests that TFPI may regulate vascular remodeling primarily through modulation of neointimal formation.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.
Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment
Authors: Barbero Fabio , Biasiolo Alessandra , Pegoraro Cinzia , Noventa Franco , Iliceto S. , Pengo Vittorio 
Published: March 2018

SummaryMitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheuma-tic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic.We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death.During a mean follow-up of 4.5 years, 1 systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, CI 0.01-2.3), and 1 minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI 0.01-2.3; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI 0.1-3.1; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment.These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF.
D-dimer Assays for the Exclusion of Venous Thromboembolism: Which Test for which Diagnostic Strategy?
Authors: de Moerloose P. 
Published: March 2018

SummaryD-dimer measurement has proven to be very useful to rule out deep vein thrombosis (DVT) and pulmonary embolism (PE) in symptomatic outpatients (1). The problem faced by many physicians is the choice and the position of the D-Dimer tests in the diagnostic work-up of patients suspected of venous thromboembolism (VTE). In the last and present issues of Thrombosis and Haemostasis, two very interesting studies addressing these questions were published.In the first paper (2), de Groot and colleagues evaluated, in a management study, the clinical utility of incorporating the SimpliRED assay in the diagnostic work-up of patients with suspected PE. Of the 245 study subjects, 59 did not receive anticoagulant therapy on the basis of a nondiagnostic lung scan, a normal D-dimer and a non-high clinical probability of PE. In the follow-up, only one patient experienced a thromboembolic event (which can be compared with the 6% of subsequent rate of VTE in the follow-up of the 54 patients with a normal perfusion lung scan). However, if SimpliRED D-dimer would have been used alone as a first exclusion step, 6 of 61 patients with proven PE had been missed (9.8%, 95% CI 3.7-20.2).
The Factor V R2 Allele: Risk of Venous Thromboembolism, Factor V Levels and Resistance to Activated Protein C
Authors: Luddington Roger , Jackson Andrew , Pannerselvam Sabapathy , Brown Karen , Baglin Trevor 
Published: March 2018

SummaryCase-control studies have yielded conflicting results regarding the relative risk of venous thromboembolism associated with the factor V R2 allele. We calculated odds ratios in 581 patients and 469 agematched controls. The odds ratio for the R2 allele in patients relative to controls was 1.21 (95% CI 0.84 to 1.74). These results do not support the hypothesis that the R2 allele is a risk factor for venous thromboembolism. There was no relationship between factor V levels and R2 carrier status. Normalised APC sensitivity ratios were not lower in carriers of the R2 allele. In an in vitro model progressive APC resistance was observed with factor V levels of 60% and less but ratios less than 2.4 (equivalent to a normalised ratio of 0.73) did not occur until factor V levels were less than 20%. The relationship between APC resistance and factor V level was not observed in a factor VIII-independent model.
Relationship of Cardiac Troponin T and Procoagulant Activity in Unstable Angina
Authors: Bardorff Margit , Schweikart Sybille , Wiegand Uwe , Kampmann Markus , Katus Hugo , Giannitsis Evangelos 
Published: March 2018

SummaryThe present study sought to determine the incidence of increased procoagulant activity in patients with unstable angina (UAP), and to evaluate the relationship between cardiac troponin T (cTnT) and molecular markers of hemostatic activation.We studied 44 patients with UAP further classified by plasma cTnT levels. All patients received an antithrombotic therapy consisting of therapeutic doses of unfractionated heparin and acetylsalicylic acid. Quantitative levels of cTnT and plasma concentrations of fibrin monomers (FM), prothrombin fragments F1+2, thrombin antithrombin III complexes (TAT), plasminogen and α2-antiplasmin were sampled serially within the first 48 h.Increased plasma concentrations of FM were detected in 45.5% of patients and were more frequently present among those with cTnT concentrations >0.1 ng/ml (13 of 18 vs 7 of 26 patients, p = 0.003). In these patients, mean plasma concentrations of FM were significantly higher than in patients with cTnT <0.1 ng/ml (7.93 ± 2.3 vs 3.12 ± 0.6 µg/ml, p = 0.02). There was a close relationship between plasma levels of cTnT and FM (r = 0.74, p <0.004), prothrombin fragments F1+2 (r = 0.71, p = 0.046) and a trend to significance was noted for TAT (r = 0.42, p = 0.055). No significant correlation was observed with markers of the fibrinolytic system (plasminogen and α2-antiplasmin). Plasma levels of cTnT >0.1 ng/ml identified a concomitant increase of hemostatic markers with a sensitivity, specificity and positive predictive value of 65, 79, and 72% for FM, 63, 76, and 67% for prothrombin fragments F1+2, and 58, 66, and 39% for TAT, respectively.In patients with UAP, cTnT identifies patients with increased procoagulant activity and is closely related to plasma levels of molecular markers of hemostatic activation. Therefore, cTnT alone or in combination with one of these markers may be helpful to identify patients requiring more potent antithrombin or antiplatelet therapy.
The Impact of Glu102Lys on the Factor X Function in a Patient with a Doubly Homozygous Factor X Deficiency (Gla14Lys and Glu102Lys)
Authors: Forberg Eva , Huhmann Iris , Jimenez-Boj Ester , Watzke Herbert 
Published: March 2018

SummaryTwo homozygous point mutations were found in a patient with factor X (FX) deficiency; One results in substitution of Lys for Gla+14 and the second causes a Lys substitution for Glu102. The proposita has a severely reduced FX coagulant activity in the extrinsic (<1% of normal) and in the intrinsic (30% of normal) system of coagulation and after activation with Russel’s viper venom (18% of normal). The FX antigen is reduced in this patient to 20% of normal. The substitution of Lys for Glu102 in FX deficiency has been reported previously in a heterozygous state in conjunction with a Lys for Gla+14 substitution and with a Pro for Ser334 substitution. The contribution of the Lys for Glu102 substitution in the observed combined FX defect in these patients was unclear. The mutation causing the Glu102Lys substitution was introduced by site directed mutagenesis into a wild-type FX cDNA, and recombinant protein was expressed in HEK 293 cells. Compared to the wild-type FX cDNA, the mutant construct had a 67% activity upon activation in the extrinsic system, 93% activity upon activation in the intrinsic system and 72% after activation with RVV. The data presented show that the substitution of Lys for Glu102 results in a minor functional defect of the FX molecule.
An Automated Heteroduplex Assay for the PlA Polymorphism of Glycoprotein IIb/IIIa, Multiplexed with Two Prothrombotic Genetic Markers
Authors: O’Connor Fiona , Fitzgerald Desmond , Murphy Ronan 
Published: March 2018

SummaryScreening for the PlA polymorphism has been made faster and simpler with the advent of heteroduplex technology. Simultaneous screening for three common prothrombotic polymorphisms PlA, factor V Leiden, and MTHFR(C677T) has been achieved with multiplex heteroduplex analysis. We describe a quick and simple method for PlA heteroduplex probe production. The probe was multiplexed with heteroduplex probes for MTHFR(C677T) and factor V Leiden polymorphisms in a one tube assay, allowing rapid automated genotyping of all three. This automated multiplex assay was applied to a cohort of 165 patients and showed excellent correlation with gel-based assays, both PAGE and RFLP. This approach will facilitate the analysis of multiple polymorphisms in complex disease in large populations.
Bovine Protein C Inhibitor Has a Unique Reactive Site and Can Transiently Inhibit Plasmin
Authors: Yuasa Hiroyuki , Tanaka Hitoshi , Hayashi Tatsuya , Wakita Toshiaki , Nakamura Hideaki , Nishioka Junji , Kawarada Yoshifumi , Suzuki Koji 
Published: March 2018

SummaryProtein C inhibitor (PCI) regulates the anticoagulant protein C pathway by neutralizing activated protein C and thrombin-thrombomodulin complex in the human hemostatic system. In this study, we cloned a full-length bovine PCI cDNA encoding a putative 19-residue signal peptide and a 385-residue mature protein; this showed 70.6%, 70.6%, 57.5% and 59.6% amino acid sequence homology with the human, rhesus monkey, rat and mouse PCIs, respectively. Bovine PCI mRNA (2.1 kb in size) was expressed strongly in the liver, and moderately in the kidney and testis, but not in other tissues tested. Bovine PCI has a putative reactive site peptide bond, Lys-Ser, that is different from the reactive site sequence (Arg-Ser) of other species’ PCI. We found that bovine PCI transiently inhibits bovine plasmin, but not human plasmin. Western blot analysis showed that the reactive site of bovine PCI is cleaved during the course of complex formation with bovine plasmin; degraded PCI is released from the complex gradually concomitant with the recovery of plasmin activity. These findings suggest that bovine PCI plays a role not only in the protein C pathway but also in the fibrinolytic activity of bovine hemostatic system.
Abbreviations: PCI, protein C inhibitor, Serpin, serine protease inhibitor, APC, activated protein C, TM, thrombomodulin.
Cellular Degradation of Free and Inhibitor-bound Tissue-type Plasminogen Activator
Authors: Camani Chantal , Gavin Olivier , Kruithof Egbert 
Published: March 2018

SummaryThe low density lipoprotein receptor-related protein (LRP) is a multiligand clearance receptor that removes free tissue-type plasminogen activator (t-PA) or complexes of t-PA with plasminogen activator inhibitor type 1 (PAI-1) from the blood circulation or the pericellular space. Co-receptors are essential for LRP-mediated clearance of several ligands (e.g. glycosaminoglycans for thrombin/protease nexin and lipoprotein lipase, and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken to investigate whether LRP-mediated t-PA clearance requires a co-receptor as well.In five cell lines from different organs and species degradation of t-PA and t-PA/PAI-1 was mediated by LRP (or LRP-like receptors). No degradation of t-PA and t-PA/PAI-1 occurred in THP-1 or U-937 human monocyte-like cells, despite the presence of functional LRP. As glycosaminoglycans can bind t-PA and PAI-1 we investigated whether they are involved in t-PA/PAI-1 degradation. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. Furthermore, CHO cells genetically deficient in glycosaminoglycans efficiently degraded t-PA/PAI-1. Thus it is unlikely that glycosaminoglycans are co-receptors for degradation of t-PA or t-PA/PAI-1.This study indicates that THP-1 and U-937 cells lack a critical component (co-receptor?) for the LRP-mediated degradation of t-PA.
Abbreviations: LRP, low density lipoprotein receptor-related protein; PAI-1, plasminogen activator inhibitor type 1; RAP, receptor-associated protein; t-PA, tissue-type plasminogen activator; u-PA, urokinase; u-PAR, urokinase receptor.
Homocysteine and Oxidized Low Density Lipoprotein Enhance Platelet Adhesion to Endothelial Cells under Flow Conditions: Distinct Mechanisms of Thrombogenic Modulation
Authors: Varon D. , Tamarin I. , Zivelin A. , Salomon O. , Shenkman B. , Savion N. , Dardik R. 
Published: March 2018

SummaryWe investigated the effects of two well established risk factors for cardiovascular disease, homocysteine and oxidized low density lipoprotein (ox-LDL), on endothelial cell thrombogenicity. For this purpose we studied platelet adhesion to human endothelial cells (EC) under flow conditions at a shear rate of 350 s−1 following EC treatment with either homocysteine or ox-LDL. Treatment of EC with either homocysteine (1 or 10 mmol/L for 16 h) or ox-LDL (100 µg/ml for 16 h) resulted in a 2-3 fold enhancement in platelet adhesion. The enhancement in platelet adhesion induced by 1 mmol/L homocysteine, but not that induced by 10 mmol/L homocysteine, was absolutely dependent on fibrin formation. Homocysteine treatment has significantly increased the cell surface tissue factor (TF) activity and slightly reduced the expression of the intercellular adhesion molecule I (ICAM-1). In contrast, ox-LDL treatment upregulated ICAM-1 expression and had no significant effect on endothelial TF activity. Neither homocysteine nor Ox-LDL affected surface expression of the αvβ3 integrin. The homocysteine-induced enhancement in platelet adhesion was almost completely abolished by blockade of the EC TF activity by a polyclonal antibody. The enhancing effect of homocysteine was also greatly reduced by inhibition of the EC αvβ3 integrin, but was not affected by blockade of EC ICAM-1. On the other hand, ox-LDL-induced enhancement in platelet – EC adhesion was greatly inhibited by blocking ICAM-1 or αvβ3, but remained unaffected by inhibition of TF activity. Preincubation of platelets with the glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist Reo-Pro has virtually abolished the enhancing effect of both homocysteine and ox-LDL. Our results suggest that homocysteine and ox-LDL might increase endothelial thrombogenicity by distinct mechanisms: homocysteine – by inducing TF activity, and ox-LDL – by upregulating ICAM-1, both of which enhance GPIIb-IIIa/fibrinogen dependent platelet adhesion to EC. The αvβ3 integrin, although not affected by EC stimulation, seems to play a crucial role in platelet-EC interaction regardless of the mechanism of EC perturbation.
Recurrent Venous Thrombosis and Markers of Inflammation
Authors: van Aken Benien , den Heijer Martin , Bos Gerard , van Deventer Sander , Reitsma Pieter 
Published: March 2018

SummaryInflammatory processes may play a key role in venous thrombosis, by inducing a procoagulant state through the action of cytokines and chemokines on monocytes and endothelial cells. Plasma concentrations of three inflammatory mediators, interleukin 6 (IL-6), interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1), that mediate the cross-talk between inflammation and coagulation, were measured in 182 subjects with recurrent venous thrombosis and 350 healthy subjects recruited through a general practice. Elevated levels of IL-6 (>90th percentile of the control group) were detected in 25.8% of the patients with venous thrombosis in comparison with 10% (by definition) of the controls [odds ratio 2.4 (95%CI 1.5-3.8)]. In 21.5% of the patients elevated plasma levels of IL-8 (>90th percentile) were determined [odds ratio 2.0 (95%CI 1.2-3.5)]. Elevated levels of MCP-1 (>90th percentile) were detected in 24.1% of the patients [odds ratio 1.9 (95%CI 1.2-3.2)]. This is the first large clinical study showing that an increase in inflammatory mediators is associated with venous thrombosis. Future prospective studies are necessary to clarify the causal nature of the inflammatory process with respect to venous thrombosis.
Exclusion of Known Protease Activated Receptors in Factor VIIa-induced Signal Transduction
Authors: Thastrup Ole , Hagel Grith , Sørensen Brit , Freskgård Per-Ola , Rao L. Vijaya , Ezban Mirella , Petersen Lars 
Published: March 2018

SummaryThe protease activity is mandatory for intracellular activities induced by coagulation factor VIIa (FVIIa), and in this way it resembles signal transduction induced by thrombin and trypsin caused by specific, proteolytic cleavage of protease activated receptors (PARs). The mechanism for FVIIa-induced signal transduction is, however, not known although a mechanism involving PAR cleavage has been deduced from studies of cytosolic Ca2+ release and p44/p42 mitogen activated protein kinase (MAPK) activation. In the present work we have examined the possibilities that i) FVIIa-induced signal transduction involves the activation of one of the four known PARs, or ii) exposure of cells to FVIIa releases a soluble ligand that is responsible for MAPK activation. For this purpose, we evaluated the effects of FVIIa, thrombin, FXa, trypsin and PAR agonist peptides on the Ca2+ release and MAPK activation in tissue factor-(TF) transfected baby hamster kidney (BHK[+TF]) cells and Madin-Darby canine kidney (MDCK) cells. FVIIa induced a significant MAPK signal in BHK(+TF) cells and in MDCK-I and -II cells whereas no MAPK activation was observed with thrombin, FXa or PAR agonist peptides. Thrombin, trypsin, PAR-1 and PAR-2 agonist peptides induced a prominent Ca2+ response in both cell types. In contrast the cells did not respond with a detectable Ca2+ signal when treated with FVIIa. These results suggest that the intracellular activity induced by FVIIa is distinctly different from that induced by trypsin, thrombin and FXa not involving any of the known PARs. Conditioned medium from BHK(+TF) cells treated with FVIIa failed to induce a MAPK response in untreated BHK(+TF) cells when FVIIa was removed by immunoadsorption from the medium prior to its transfer to the untreated BHK(+TF) cells. Although it is not possible entirely to exclude a transient response close to the cell surface, the data suggest that the intracellular response was not induced by an autocrine release of a soluble mediator to the medium.