bluuebunny/crossref_metadata_2025_split huggingface dataset:
Travel and the risk of symptomatic venous thromboembolism
Authors: ten Wolde Marije , Kraaijenhagen Roderik , Schiereck Jan , Hagen Petronella , Mathijssen Joost , Mac Gillavry Melvin , Koopman Maria , Büller Harry 
Published: March 2018

SummaryWhether long-distance travel and symptomatic venous thromboembolism (VTE) are associated is debated. On the basis of the available literature a fair risk estimate cannot be obtained. We estimated an accurate odds ratio for the relationship between recent travelling and symptomatic VTE.From three case-control studies consisting of 788 and 170 patients with clinically suspected deep vein thrombosis (DVT) and 989 patients with clinically suspected pulmonary embolism (PE) referred for diagnostic work-up, a pooled odds ratio for the relation between travel and symptomatic VTE was calculated. Cases were patients in whom the diagnosis was confirmed according to a diagnostic management strategy, whereas controls were patients in whom the diagnosis was excluded and who had an uneventful clinical follow-up. Patients were seen in the period April 1997 to September 2000. Travel history was recorded prior to diagnostic work-up.The pooled odds ratio for the association between any travel and symptomatic venous thromboembolism was 0.9 (95% CI: 0.6-1.4). The median travel time was 7 h (quartile range 4 to 10 h). Separate analyses performed for different types of transport (plane, car, bus or train) yielded comparable odds ratios. The analysis for duration of travelling showed an increased odds ratio of 2.5 (95% CI: 1.0-6.2) in the category of 10-15 h of travelling.This study shows that the average traveller does not have an increased risk for symptomatic venous thromboembolism. Only very long travelling (more than 10 h) may be associated with venous thromboembolic disease.
CD32-dependent platelet activation by a drug-dependent antibody to glycoprotein IIb/IIIa antagonists
Authors: Pedicord Donna , Dicker Ira , O’Neil Karyn , Breth Leah , Wynn Richard , Hollis Greogory , Billheimer Jeffrey , Stern Andrew , Seiffert Dietmar 
Published: March 2018

SummaryThrombocytopenia is observed with a frequency of up to 2% in patients treated with glycoprotein (GP) IIb/IIIa antagonists. We recently provided evidence that thrombocytopenia is caused by antibody binding to drug-induced conformational changes in GP IIb/IIIa. Here, we report that a murine monoclonal antibody binds to GP IIb/IIIa in an antagonist-dependent manner and activates platelets. Platelet stimulation is associated with a disruption of the phospholipid asymmetry, resulting in the assembly of catalytic active intrinsic Xase and prothrombinase complexes. Further mechanistic studies revealed that this response is (I) mediated in cis, (II) not associated with the formation of pro-thrombotic microparticles, and (III) requires intact platelet signaling and (IV) is blocked by increases in cAMP. The prothrombotic response is not observed using F(ab’)2 fragments and is blocked by incubation of platelets with neutralizing antibodies to the platelet FcγRIIa receptor (CD 32). Taken together, these observations suggest that GPIIb/IIIa antagonist-dependent antibody binding to the platelet fibrinogen receptor has the propensity to lead to CD32-mediated platelet activation and accelerated platelet clearance, leading to thrombocytopenia.
Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin
Authors: Hudek Renata , Piazolo Lukas , Haase Karl , Borggrefe Martin , Huhle Günter , Fischer Karl-Georg , Liebe Volker 
Published: March 2018

SummaryRecombinant hirudin (r-hirudin) is a potent direct thrombin inhibitor with immunogenic properties. Anti-hirudin antibodies (aHAb) are detected in up to 74% of patients treated with r-hirudin for more than 5 days. aHAb may alter the pharmaco-kinetics and pharmacodynamics of r-hirudin.The effects of aHAb on the pharmacokinetics of r-hirudin were investigated in rats receiving r-hirudin intravenously either without aHAb (controls), 15 min after intravenous administration of non-specific antibodies or aHAb, and after pre-incubation with aHAb. When both were compared to controls and pre-treatment with non-specific antibodies, aHAb significantly altered the pharmacokinetics of r-hirudin with similar effects in both approaches: In the presence of aHAb, the volume of distribution in a steady state and total plasma clearance were diminished, while the half-life of elimination was prolonged. Both the maximum r-hirudin plasma concentration and the area under the curve were increased. In addition, r-hirudin filtration by high-flux hemodialyzer membranes (polysulfone, AN69) was investigated 1) in the absence of aHAb, 2) in the presence of non-specific mouse antibodies, and 3) in the presence of three monoclonal aHAb. In the absence of aHAb, both hemodialyzers allowed for significant r-hirudin filtration. Non-specific mouse antibodies did not markedly affect r-hirudin filtration. By contrast, all three aHAb almost completely hindered r-hirudin filtration. aHAb varied in their capacity to neutralize r-hirudin. In conclusion, aHAb markedly alter the pharmacokinetics of r-hirudin leading to r-hirudin accumulation. In the presence of aHAb, hemofiltration does not allow for rapid reduction of r-hirudin concentration. aHAb are capable of modifying pharmacodynamics of r-hirudin. Close monitoring of aHAb-positive patients treated with r-hirudin is considered mandatory.
A new monoclonal antibody, mAb 204-11, that influences the binding of platelet GPVI to fibrous collagen
Authors: Mizuguchi Jun , Kawashima Sachiko , Nagamatsu Michiko , Miura Yoshiki , Nakagaki Tomohiro , Ito Katsuaki , Jung Stephanie , Moroi Masaaki 
Published: March 2018

SummaryThe newly identified platelet collagen receptor glycoprotein VI binds to fibrous collagen, inducing platelet activation. Several antibodies against GPVI have been reported, including a patient’s auto-antibodies, that activates platelets through their ability to crosslink this glycoprotein. We have developed a monoclonal antibody (mAb) against GPVI using the recombinant extracellular domain of GPVI as an antigen. This antibody, mAb 204-11, induced platelet aggregation and tyrosine phosphorylation of proteins similar to those induced by GPVI-reactive proteins, collagen and convulxin. Its interaction with GPVI was analyzed by measuring the effect of the antibody on GPVI binding to collagen using a dimeric form of recombinant GPVI, GPVI-Fc2. MAb 204-11 inhibited the binding of GPVI-Fc2 to fibrous collagen particles, but enhanced the GPVI binding to immobilized collagen, suggesting that the antibody binds to a region near the collagen binding site of GPVI. MAb 204-11 also inhibited the GPVI binding to convulxin at a low concentration, but not completely. Since mAb 204-11 reacts specifically with GPVI and is applicable for immunoblotting and immunoprecipitation, this antibody would be useful for studies on GPVI.
Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases
Authors: Jungermann Kurt , Görlach Agnes , Kietzmann Thomas 
Published: March 2018

SummaryMitogen-activated protein kinases (MAPKs) and protein kinase B (PKB) mediate growth and stress signals and have been implicated in the hypoxic response. Under hypoxic conditions, the expression of plasminogen activator inhibitor-1 (PAI-1) is mainly controlled by the hypoxia-inducible factor HIF-1. However, the role of MAPKs and PKB in HIF-1-mediated PAI-1 regulation is not clear.Treatment with the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, but not with the MEK1 inhibitor PD98059, abrogated hypoxia-dependent PAI-1 induction in HepG2 cells. Consistently, overexpression of PKB or of the p38 upstream kinases MKK6 and MKK3 and of JNK, but not of ERK, enhanced PAI-1 mRNA levels. In MKK3-,MKK6- and PKB-expressing cells luciferase (Luc) activities from a hypoxia-inducible PAI-1-Luc construct or from a HIF-dependent Luc construct and, concomitantly, HIF-1α protein levels were enhanced. These findings indicate that p38- and PKB-dependent signalling pathways contribute to enhanced PAI-1 levels in the hypoxic response.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.
Role of Gender and Genetic Variance in Plasminogen Activator Inhibitor-1 Secretion from Human Adipose Tissue
Authors: Wahrenberg Hans , Eriksson Per , Arner Peter , Van Harmelen Vanessa 
Published: March 2018

SummaryGender and the 4G/5G polymorphism in the plasminogen activator inhibitor 1 (PAI-1) gene are believed to play a role in the regulation of plasma PAI-1 activity. Adipose tissue has been found to be an important source of PAI-1. The possible influence of gender and the 4G/5G polymorphism in the PAI-1 gene on PAI-1 secretion from abdominal subcutaneous adipose tissue was investigated in 59 women and 32 men. The subjects were apparantly healthy, although they differed markedly inter-individually in body mass index (21-53 kg/m2). The 4G/5G polymorphism did not influence the adipose secretion rate of PAI-1 or plasma PAI-1 activity. There was no gender difference in the adipose secretion of PAI-1. In multiple regression, including body mass index (BMI), waist-to-hip ratio (WHR), plasma insulin and plasma triglycerides as the independent and adipose PAI-1 secretion as the dependent variable, only BMI and plasma triglycerides correlated independently with adipose PAI-1 secretion (r = 0.54, p <0.05; r = 0.51, p <0.05, respectively). Men had a two times higher plasma PAI-1 activity than women (p <0.05). This gender difference was mainly due to gender differences in WHR. In multiple regression analysis, BMI and WHR were identified to be independently correlated with plasma PAI-1 activity (r = 0.60, p <0.05; r = 0.52, p = 0.01, respectively). In conclusion, neither gender nor the 4G/5G polymorphism in the PAI-1 gene are associated with secretion of PAI-1 from abdominal subcutaneous adipose tissue.
Effects of Fluvastatin and Bezafibrate Combination on Plasma Fibrinogen, t-plasminogen Activator Inhibitor and C Reactive Protein Levels in Coronary Artery Disease Patients with Mixed Hyperlipidaemia (FACT Study)
Authors: Cofrancesco E. , Boschetti C. , Cortellaro F. , Mancini M. , Mariani M. , Paoletti R. , Cortellaro M. ,   the FACT Study Centers
Published: March 2018

SummaryWe studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen, t-plasminogen activator inhibitor (PAI-1) and C reactive protein (CRP) in patients with coronary artery disease (CAD) and mixed hyperlipidaemiaIn this randomised, double blind, multicentre trial 333 patients with stable angina pectoris or previous myocardial infarction or coronary revascularisation and mixed hyperlipidaemia (LDL-cholesterol 135-250 mg/dl and triglycerides (TG) 180-400 mg/dl) were randomised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks.Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate (−14 and −16%) and with bezafibrate monotherapy (−9%). No significant reduction was observed after fluvastatin monotherapy (−4%). No significant changes were observed in PAI-1 and CRP plasma levels. Combination therapy significantly decreased both LDL-C and TG, and significantly increased HDL-C.The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease.
The Role of Vitamin B12 in Fasting Hyperhomocysteinemia and Its Interaction with the Homozygous C677T Mutation of the Methylenetetrahydrofolate Reductase (MTHFR) Gene
Authors: Coppola Antonio , Madonna Pasquale , Fermo Isabella , Pagano Anna , Mazzola Giuseppina , Galli Laura , Cerbone Anna , D’Angelo Armando 
Published: March 2018

SummaryTotal fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 ± 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 ± 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 µM in men and >15 µM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78–5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42; 0.84–2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61–14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = −0.42 and −0.25) than with the 677CC or CT MTHFR genotype (r = −0.37 and −0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 ± 206 vs. 408 ± 185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p ≤0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p ≤0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B12 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.
Proteolytic Modulation of Thrombopoietin Activity: Comparison of Thrombin, Plasmin, and Urokinase
Authors: Aramaki Kaelen , Reiner Alexander 
Published: March 2018

SummarySeveral observations suggest that limited proteolysis of full-length 70 kD human thrombopoietin (Tpo) may be important for Tpo biology. Recently, it was reported that thrombin cleaves full-length recombinant human Tpo (rhTpo) sequentially at two sites, Arg195 within the glycan domain followed by Arg117 within the cytokine domain, and that these cleavages modulate Tpo activity in vitro. We demonstrate that urokinase and plasmin also cleave rhTpo in a time-dependent manner. Urokinase cleavage is confined to the glycan domain, and generates a 35 kD N-terminal fragment that contains the intact cytokine domain, and is associated with increased Tpo activity. In contrast, plasmin cleaves Tpo sequentially at two specific sites (Arg205 within the glycan domain followed by Lys52 within the cytokine domain), and is associated with a marked decrease in Tpo activity. These proteolytic events have potential implications for regulation of Tpo activity in vivo.
A Case of Congenital Afibrinogenemia: Fibrinogen Hakata, a Novel Nonsense Mutation of the Fibrinogen γ-Chain Gene
Authors: Iida Hiroko , Ishii Eiichi , Nakahara Mutsuko , Urata Michiyo , Wakiyama Machiko , Kurihara Masako , Watanabe Kumiko , Kai Takeshi , Ihara Kenji , Kinoshita Sachiko , Hamasaki Naotaka 
Published: March 2018

SummaryCongenital afibrinogenemia due to a novel homozygous nonsense mutation of the fibrinogen γ-chain gene, fibrinogen Hakata, was found in an 18-year-old Japanese girl who had received supplemental fibrinogen therapy since she was 4 months old. The plasma fibrinogen concentrations of the proband were measured as less than 10 mg/dl by a functional method and less than 17 mg/dl by an immunological method. Fibrinogen concentrations of her family were in the range of 94-164 mg/dl. The proband and her family had no other clinical symptoms.Genomic DNA of the proband and her family was isolated from leukocytes, and all exons of fibrinogen subunits and their intron/exon boundaries were analyzed. A genetic mutation, a guanine-to-thymine (G-to-T) transversion at the nucleotide position of 5860, was identified on exon 7 of the γ-chain gene. This mutation changed the codon for the 231st residue of the γ chain from GAG (Glu) to TAG (stop). No other mutation was observed. Aα, Bβ and γ chains were observed in plasma of the heterozygous family members. However, only a trace amount of Aα chain and no γ chain was detected in the plasma of the proband.
Monoclonal Antibodies against Platelet Membrane Glycoproteins IIb/IIIa and Ibα Inhibit Platelet Dependent Thrombin Generation by Different Mechanisms
Authors: Metcalfe Paul , Goodall Alison , Gray Elaine , Thomas Stephen 
Published: March 2018

SummaryThe antithrombotic effect of antiplatelet agents is principally due to their anti-aggregatory action, but these agents may also interfere with coagulation. We have investigated the effect of monoclonal antibodies (MAb) to platelet membrane glycoproteins (GP) IIb/IIIa and Iba on thrombin generation.Antibodies to platelet membrane glycoprotein IIb/IIIa (RFGP56 and c7E3) were shown to inhibit platelet-mediated thrombin generation stimulated by both intrinsic and extrinsic methods. An antibody to GP Ibα (RFGP37) also inhibited thrombin generation in these systems.FITC-annexin V was used to determine the effect of these antibodies on the exposure of procoagulant phospholipids on the platelet membrane, and it was found that the anti-IIb/IIIa antibodies reduced this, whereas the anti-Ibα antibody caused an increase.We conclude that our monoclonal antibodies against platelet membrane glycoproteins IIb/IIIa and Ibα inhibit platelet dependent thrombin generation by different mechanisms.
Tissue Factor Is Rapidly Elevated in Plasma Collected from the Pericardial Cavity during Cardiopulmonary Bypass
Authors: Philippou Helen , Adami Antonella , Davidson Simon , Pepper John , Burman John , Lane David 
Published: March 2018

SummaryThere is growing evidence that the tissue factor/factor VIIa pathway of coagulation is enhanced during cardiopulmonary bypass. Hitherto, available evidence has suggested that upregulated monocyte bound tissue factor is made available, either in the blood collected from the site of surgery or on circulating cells. However, cellular upregulation is slow, while generation of factor VIIa in blood collected from the pericardial cavity is rapid. We have therefore investigated the possibility of an alternative source of tissue factor, plasma (as opposed to cellular) tissue factor in blood samples taken from the central vein catheter (systemic circulation) and collected from the pericardial cavity during cardiopulmonary bypass. Six patients undergoing first time cardiopulmonary bypass grafting were studied. Tissue factor antigen was found to be rapidly elevated (by 15 min) in the pericardial plasma, ∼5-fold above systemic levels (p <0.004). Similar elevations were found in markers of coagulation activation, factor VIIa antigen (p = 0.066), prothrombin fragment F1+2 (p <0.003) and thrombin-antithrombin complex (p <0.03). To explore whether plasma tissue factor was (or had been) functionally active, factor VIIa was measured also with the soluble tissue factor functional assay after removal of heparin. Functional factor VIIa activity fell significantly in the systemic circulation, probably due to the heparin-induced increase (∼15-fold) in tissue factor pathway inhibitor (TFPI), but was elevated in pericardial blood compared with that taken from the central line catheter (p <0.006). These results demonstrate that both components of the activation complex for the extrinsic pathway of coagulation are rapidly generated in pericardial blood during bypass.
Plasma Concentration of von Willebrand Factor in Acute Myocardial Infarction
Authors: Kim Jae-Young , Aoki Naoto , Abe Sumihisa , Ichikawa Noriko , Yoshida Minako , Nagaoka Yuta , Handa Shunnosuke , Sakai Hiroyuki , Goto Shinya 
Published: March 2018

SummaryRecent investigations have revealed the crucial role of von Willebrand factor (vWF) in platelet thrombus formation under flow conditions. The plasma concentrations of vWF were measured together with various hemodynamic and hemostatic parameters in 51 cases of acute myocardial infarction. In 10 randomly selected cases, the plasma concentrations and distribution of multimers vWF were serially determined after reperfusion therapy by percutaneous transluminal coronary angioplasty (PTCA). The vWF concentration at the onset of the acute myocardial infarction was significantly higher than in an age-matched control group (vWF AG: 18.7 ± 1.2 µg/ml vs. 10.3 ± 0.5 µg/ml, p = 8.43×10− (12), mean ± SE). Simultaneous determination of hemodynamic and hemostatic parameters revealed that the only two parameters that were significantly correlated with the patients` plasma vWF concentrations were their pulmonary capillary wedge pressure (PCWP) and heart rate, suggesting a relationship between hemodynamic changes induced by the onset of myocardial infarction and the vWF plasma concentrations. Serial determinations revealed that the vWF concentrations had not changed 1 h after reperfusion therapy, but that they significantly increased by 24 to 72 h. The distribution of the larger multimers of vWF also increased in the acute and subacute phase. The vWF concentration and multimer distribution normalized 14 days after the onset of the myocardial infarction. Our findings suggest that the vWF concentration increased in acute myocardial infarction patients, possibly in association with the hemodynamic deterioration that occurs in acute myocardial infarction.