bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of fibrin monomers in optimizing the diagnostic work-up of deep vein thrombosis
Authors: Haas Fred , Agterof Mariette , Vos Marike , Biesma Douwe , Schutgens Roger 
Published: June 2007

SummaryDespite the use of a clinical score and D-dimers to exclude deep vein thrombosis (DVT), the majority of patients still need repeated ultrasound (US).The aim of the study was to investigate whether fibrin monomers (FMs), as markers of thrombin generation, have additional value in the diagnosis of DVT. This is a posthoc analysis of 464 outpatients, participants in a management study using D-dimers (Tina-Quant® ) and a clinical score in the exclusion of DVT. Two new FM assays (Auto LIA-FM® and IATRO SF®, Japan) were performed. Overall sensitivity, negative predictive value (NPV) and specificity of the D-dimer test were 98%, 98% and 42%.The optimal cut-off point for the Auto LIAFM test was ≤ 3 µ g/ml with values of 88%, 88% and 59%, respectively. The IATRO SF test had an optimal cut-off point of ≤ 2 µ g/ ml with values of 92%, 81 and 22%, respectively.The NPV of a non-high clinical score and a normal D-dimer (n=97) was 100%. In patients with a high clinical score (n=160), the NPV of the D-dimer was 88%. In these patients, a single US combined with a normal D-dimer or FM test had an equal NPV as serial US (100 versus 98%, respectively) and lead to a reduction in the need for US by 36–53%, respectively. In patients with abnormal D-dimer concentrations (n=343), a normal US combined with a normal Auto LIA-FM test had a NPV of 97%,which was also true for serial US.This could lead to a reduction in the need for US by 45%. The present studied FMs are inferior to theTina-Quant D-dimer test when used as primary screening tool to exclude DVT.Adding these FMs to patients with a normal Tina-Quant D-dimer has no benefit. In patients with a high pretest clinical probability score, a single US in combination with a normal D-dimer or FM test might be as safe as serial US. In patients with abnormal D-dimer concentrations and a normal US, a normal FM test might be able to replace the second US.
Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression
Authors: Feng Yuxi , vom Hagen Franziska , Pfister Frederick , Djokic Snezana , Hoffmann Sigrid , Back Walter , Wagner Patrick , Lin Jihong , Deutsch Urban , Hammes Hans-Peter 
Published: June 2007

SummaryAngiopoietin-2 (Ang2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularizations. Ang2 is also involved in incipient diabetic retinopathy, as it may cause pericyte loss. To investigate the impact of Ang2 on developmental and hypoxia-induced angiogenesis, we used a transgenic mouse line overexpressing human Ang2 in the mouse retina. Transgenic mice displayed a reduced coverage of capillaries with pericytes (-14 %; p<0.01) and a 46% increase of vascular density of the capillary network at postnatal day 10 compared to wild type mice. In the model of oxygen-induced retinopathy (OIR), Ang2 overexpression resulted in enhanced preretinal (+103%) and intraretinal neovascularization (+29%). Newly formed intraretinal vessels in OIR were also pericyte-deficient (-26 %; p<0.01). The total expression of Ang2 in transgenic mice was seven-fold, compared with wild type controls. Ang2 modulated expression of genes encoding VEGF (+65%) and Ang1 (+79%) in transgenic animals. These data suggest that Ang2 is involved in pericyte recruitment, and modulates intraretinal, and preretinal vessel formation in the eye under physiological and pathological conditions.
High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes
Authors: Frere Corinne , Quilici Jacques , Morange Pierre-Emmanuel , Nait-Saidi Lyassine , Mielot Christopher , Bali Laurent , Lambert Marc , Alessi Marie-Christine , Bonnet Jean-Louis , Cuisset Thomas 
Published: June 2007

SummaryHigh post-treatment platelet reactivity (HPPR= adenosine diphosphate [ADP] 10 µM-induced platelet aggregation > 70%) identifies low responders to dual antiplatelet therapy with increased risk of recurrent cardiovascular (CV) events after stenting for non-ST elevation acute coronary syndromes (NSTEACS). This study was designed to compare the incidence of periprocedural myocardial infarction (MI) after stenting for NSTEACS patients between non-responders to dual antiplatelet therapy defined by HPPR and normo-responders. One hundred ninety NSTE-ACS consecutive patients undergoing coronary stenting were included in this prospective study. They received 250 mg aspirin and a 600 mg loading dose of clopidogrel at least 12 hours (h) before percutaneous coronary intervention (PCI). A single post-treatment blood sample was obtained before PCI to analyze maximal intensity of ADP-induced platelet aggregation, and troponin levels were analyzed before PCI, and 12 and 24 h after PCI. Troponin I was considered elevated if > 0.4 ng/ ml. HPPR was present in 22% of patients (n=42). Periprocedural MI occurred significantly more frequently in patients with HPPR than in the normo-responders (43% vs. 24%, p=0.014). After being correlated with recurrent ischemic events after stenting for NSTE-ACS, the HPPR seems to be also a marker of increased risk of periprocedural MI for NSTE-ACS patients.
Recombinant annexin-2 inhibits the progress of diabetic nephropathy in a diabetic mouse model via recovery of hypercoagulability
Authors: Ishii Hideto , Hiraoka Megumi , Tanaka Akira , Shimokado Kentaro , Yoshida Masayuki 
Published: June 2007

SummaryDiabetic nephropathy, a major complication of diabetes mellitus that leads to mortality, has been shown to involve a dysregulation of the coagulation system. Annexin-2, a co-receptor for plasminogen and tissue plasminogen activator on endothelial cells, is one of the molecules required to maintain the antithrombogenic properties of endothelial cells. Previously, we showed that recombinant annexin-2 protein (rAN II) modulated impaired fibrinolytic activity in the carotid arteries of rats. In the present study, to investigate its protective effects against diabetic nephropathy, rAN II was administered to KK-Ay mice, a murine model of type 2 diabetes, for eight weeks, and albuminuria, kidney size, and histological glomerular lesions were investigated. The mean weight of kidneys from KK-Ay mice treated with rAN II was significantly less than that of those treated with PBS (control) (p<0.02). Furthermore, the level of albuminuria observed in rAN II-treated KK-Ay mice was significantly less than that of the control group (rAN II, 0.90+/-0.12 µg/day; PBS, 1.55+/-0.31 µg/day; p<0.01); also, the area of diffuse glomerular lesions was significantly smaller (rAN II, 41.51+/-4.54%; PBS, 81.81+/-8.10%; p<0.01). Bleeding time, prothrombin time (PT), and active partial thromboplastin time (APTT) did not significantly differ between the two groups. Our results suggest that rAN II may inhibit the progression of diabetic nephropathy in KK-Ay mice without influencing the coagulation system, indicating that annexin-2 may be considered as a possible new therapeutic tool for patients with diabetic nephropathy.
Genetic variation in estrogen receptor, C-reactive protein and fibrinogen does not predict the plasma levels of inflammation markers after longterm hormone replacement therapy
Authors: Madsen Jonna , Langdahl Bente , Bladbjerg Else , Tofteng Charlotte , Abrahamsen Bo , Rejnmark Lars , Brixen Kim , Christensen Kaare , Jespersen Jørgen , Kristensen Søren , de Maat Moniek 
Published: June 2007

SummaryMarkers of inflammation, such as C-reactive protein (CRP) and fibrinogen, are associated with the risk of atherothrombosis. Plasma levels of these markers of inflammation are affected by hormone replacement therapy (HRT) and modulated by smoking. We studied whether genetic variation in the estrogen receptor- 1 (ESR1), CRP and fibrinogen-β genes influences the plasma levels of inflammation markers after HRT. Plasma CRP and fibrinogen were measured after five years follow-up in healthy postmenopausal women (per-protocol group) who were randomised to hormone therapy (n=187) or no treatment (n=249). The effect of HRT, smoking and genetic variations in ESR1 (PvuII and XbaI), CRP (1444C/T) and fibrinogen-β ( FGB, –455G/A) were determined. The plasma concentration of CRP was higher in the HRT group than in the control group (2.03 mg/l and 1.41 mg/l, respectively; p < 0.001), while the concentration of fibrinogen was lower in the HRT group than in the control group (3.02 g/l and 3.20 g/l, respectively; p < 0.001), indicating that it is unlikely that inflammation is the common underlying pathway. There was a significant interaction between smoking and HRT on the ibrinogen (p=0.02), but not on the CRP concentration (n.s.). Genetic polymorphisms in ESR1, CRP and fibrinogen were not associated with an effect of HRT on the CRP and fibrinogen plasma levels, and no significant interaction with smoking was observed. In conclusion, higher plasma levels of CRP and lower plasma levels of fibrinogen were observed in women using HRT; however, genetic polymorphisms in ESR1, CRP and FGB were not associated with these effects of HRT.
Sequential adhesion of platelets and leukocytes from flowing whole blood onto a collagen-coated surface: Requirement for a GpVI-binding site in collagen
Authors: Butler Lynn , Metson-Scott Tom , Felix Jo , Abhyankar Anita , Rainger G. , Farndale Richard , Watson Stephen , Nash Gerard 
Published: June 2007

SummaryThe adhesion of leukocytes to immobilised platelets may contribute to inflammatory and thrombotic responses in damaged tissue. To investigate the conditions under which platelets and leukocytes might be deposited together in vessels, we perfused fluorescently-labelled whole blood through glass capillaries coated with various collagen preparations. Video-microscopic observations of the surface showed that platelets formed numerous, individual, rolling and stationary attachments to surfaces coated with acid-soluble, monomeric collagen. However, leukocyte interactions with the deposited platelets were rare. If the blood was washed out, the adherent platelets became more activated, and many rolling adherent leukocytes were observed if a second bolus of blood was perfused over them. This suggested that platelet activation had initially been inadequate to support leukocyte capture. Next, fibrillar collagen was adsorbed to the capillaries to present an ordered array of peptide motifs to platelet receptor glycoprotein (Gp)VI and transduce an activating signal. In this case, platelets were deposited in discrete, stable aggregates and the bound platelets captured many flowing leukocytes.Alternatively, acid-soluble collagen was seeded with collagen-related peptide (CRP) known to contain a GpVI-binding motif.Again, platelet adhesion became stable, and numerous flowing leukocytes were captured.Addition of antibody against GpVI or against P-selectin greatly reduced leukocyte adhesion to the platelets. Thus, in whole blood, platelets binding to exposed collagen need to be activated through GpVI in order to expose sufficient P-selectin to allow efficient capture of flowing leukocytes to take place.
Factor XIII activation peptide is released into plasma upon cleavage by thrombin and shows a different structure compared to its bound form
Authors: Schroeder Verena , Vuissoz Jean-Marc , Caflisch Amedeo , Kohler Hans 
Published: June 2007

SummaryThe first step of coagulation factor XIII (FXIII) activation involves cleavage of the FXIII activation peptide (FXIII-AP) by thrombin. However, it is not known whether the FXIII-AP is released into plasma upon cleavage or remains attached to activated FXIII. The aim of the present work was to study the structure of free FXIII-AP, develop an assay for FXIII-AP determination in human plasma, and to answer the question whether FXIII-AP is released into plasma. We used ab-initio modeling and molecular dynamics simulations to study the structure of free FXIII-AP. We raised monoclonal and polyclonal antibodies against FXIII-AP and developed a highly sensitive and specific ELISA method for direct detection of FXIII-AP in human plasma. Structural analysis showed a putative different conformation of the free FXIII-AP compared to FXIII-AP bound to the FXIII protein. We concluded that it might be feasible to develop specific antibodies against the free FXIII-AP. Using our new FXIII-AP ELISA, we found high levels of FXIII-AP in in-vitro activated plasma samples and serum. We showed for the first time that FXIIIAP is detached from activated FXIII and is released into plasma, where it can be directly measured. Our findings may be of major clinical interest in regard to a possible new marker in thrombotic disease.
Sex-specific, independent associations of insulin resistance with erythrocyte sedimentation rate in apparently healthy subjects
Authors: Hernández-Aguado Ildefonso , Jarrín Vera Inmaculada , Recasens Mónica , Esteve Eduardo , Casamitjana Roser , Ricart Wifredo , Fernández-Real José , López-Bermejo Abel 
Published: June 2007

SummaryInsulin resistance and erythrocyte sedimentation rate (ESR, a non-specific marker of inflammation) are known risk factors for cardiovascular disease. Although obesity is associated with increased ESR, it is unclear whether insulin resistance is associated with ESR in humans. The relationship between insulin resistance and ESR was studied in a cross-sectional, health-area based study of 140 (89 men and 51 women) apparently healthy Caucasians subjects. ESR, additional inflammatory markers [soluble tumor necrosis alpha receptors 1 and 2 (sTNFR1 and sTNFR2); C-reactive protein (CRP)], and insulin sensitivity ( S I, frequently sampled intravenous glucose tolerance test with minimal model analysis) were assessed in all subjects. An interaction with sex was documented in the relationship between ESR and both insulin resistance and obesity (p < 0.05), as log ESR correlated with log S I in men (r= –0.29, p = 0.009), but not in women (r= –0.14, p = 0.33), and correlated with body mass index (BMI) in women (r=0.49, p= < 0.0001), but not in men (r=0.15, p = 0.16). On multivariate analyses, these associations proved to be independent of known covariates, such as age, hematocrit, smoking and additional inflammatory markers in both men and women. In a replication study, variables independently associated with ESR were also insulin resistance (homeostasis model assessment) in men and obesity markers (either BMI or fat mass) in women. In conclusion, ESR is independently associated with either insulin resistance or obesity in a sex-specific manner. These findings contribute to explain the known relationship of this inflammatory marker with cardiovascular disease.
Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: The Rotterdam Study
Authors: Kardys Isabella , Uitterlinden André , Hofman Albert , Witteman Jacqueline , de Maat Moniek 
Published: June 2007

SummaryFibrin network structure has been correlated with coronary disease. Fibrinogen γ and α (FGG and FGA) gene haplotypes (chromosome 4q28) may be associated with fibrin network structure, and thereby with rigidity of the fibrin clot and sensitivity of the fibrin clot to the fibrinolytic system. Through these mechanisms they may influence risk of cardiovascular disease. We set out to investigate the relation between combined fibrinogen FGG and FGA gene haplotypes, representing the common variation of the fibrinogen FGG and FGA genes, coronary events and measures of coronary and extracoronary atherosclerosis. The study was embedded in the Rotterdam Study, a prospective populationbased study among men and women aged ≥ 55 years. Common haplotypes were studied using seven tagging SNPs across a 30-kb region with the FGG and FGA genes. Incident coronary events were registered, and carotid intima-media thickness, carotid plaques, ankle-arm index, aortic calcification and coronary calcification were assessed. Seven haplotypes with frequencies >1% covered 97.5% of the genetic variation. In 5,667 participants without history of coronary heart disease (CHD), 733 CHD cases occurred during a median follow-up time of 11.9 years. Fibrinogen gene haplotypes were not associated with coronary events. Fibrinogen gene haplotypes did not show a consistent association with measures of coronary and extracoronary atherosclerosis. In conclusion, fibrinogen FGG and FGA gene haplotypes are not associated with coronary events, coronary atherosclerosis or extracoronary atherosclerosis. Confirmation of these findings by future population-based studies is warranted.
A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity – a staphylokinase variant
Authors: Stankiewicz Adrian , Rozmyslowicz-Szermńska Wioletta , Mogielnicki Andrzej , Gromotowicz Anna , Buczko Wlodzimierz , Oszajca Katarzyna , Bartkowiak Jacek , Chabielska Ewa , Szemraj Janusz 
Published: June 2007

SummaryThe recombinant protein SAK-RGD-K2-Hir is characterized by its fibrin-specific properties of plasminogen activation combined with antithrombin and antiplatelet activities. It was previously shown in our in-vitro studies to be a more potent and faster-acting thrombolytic agent compared with standard r-SAK. In order to document the effects of the thrombolytic potential of SAKRGD- K2-Hir we examined this protein in an electrically induced carotid artery thrombosis model and stasis-induced venous model in rats. In the arterial thrombosis model, a bolus injection of SAK-RGD-K2-Hir was less effective than rt-PA and r-SAK. However, the most effective in the improvement and maintenance of carotid patency and in arterial thrombus mass reduction was SAK-RGD-K2. In contrast, all r-SAK derivatives reduced venous thrombus weight significantly in comparison to r-SAK and r-Hir. However, the most observable decrease in thrombus weight was obtained after application of recombinant proteins containing the r-Hir.The bleeding time was significantly prolonged in the animals treated with proteins containing r-Hir at a dose of 1.0 mg/kg.There were no observable changes in plasma fibrinogen concentration.In conclusion,our findings show thrombolytic activity in intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hir in rats.Although this protein compares favourably with r-SAK in rat venous thrombolysis, we were unable to confirm the beneficial effects of SAK-RGDK2- Hir over r-SAK and rt-PA in the carotid artery thrombolysis model. Furthermore, our results also suggest that SAKRGD- K2-Hir bears a risk of bleeding, but this may be true for higher doses.
Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome
Authors: Cuisset Thomas , Frere Corinne , Quilici Jacques , Morange Pierre-Emmanuel , Saut Noémie , Romero-Barra Marie , Camoin Laurence , Lambert Marc , Juhan-Vague Irène , Bonnet Jean-Louis , Alessi Marie-Christine 
Published: June 2007

SummaryVariability in platelet response to antiplatelet therapy and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. It was the aim of the present study to assess whether the response to aspirin and clopidogrel may be influenced by the 807 C/T polymorphism of the glycoprotein Ia (GpIa) gene in patients with non-ST elevation acute coronary syndrome (NSTE ACS). Six hundred one NSTE ACS patients were included in our study and were divided into three groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples were
drawn. Post-treatment platelet reactivity was assessed by post treatment ADP 10 µM-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression. Non-response to dual antiplatelet therapy was defined by high post-treatment platelet reactivity (HPPR= ADP-Ag>70%). Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameters profiles was observed within patients having the same genotype, for ADP-Ag (p=0.33), PRIVASP (p=0.72) and P-selectin expression (p=0.37). The genotype frequencies of the 807 C/T polymorphism of the GpIa gene were similar in responders and non-responders defined by persistent HPPR (p=0.104). In conclusion, our study did not show any influence of 807 C/T polymorphism of GpIa gene on post-treatment platelet reactivity assessed by ADP-Ag, PRI VASP or P-selectin expression in 601 NSTE ACS patients.
Appropriateness of diagnostic strategies for evaluating suspected venous thromboembolism
Authors: Arnason Thomas , Wells Philip , Forster Alan 
Published: June 2007

SummaryIt was the objective of this study to determine the proportion of patients who undergo an appropriate diagnostic work-up following a D-dimer test performed to evaluate suspected pulmonary embolism (PE) or deep vein thrombosis (DVT). We performed a retrospective cohort study at a tertiary care hospital. We included patients if they underwent D-dimer testing between 2002 and 2005, if the D-dimer was performed for evaluation of VTE, and if the D-dimer test was successful. We classified: the patients’ clinical probability of DVT or PE according to theWells models,the imaging results,and the appropriateness of the testing algorithm. Of 1,000 randomly selected patients, 863 met our study criteria. Seven hundred nineteen patients (83%) had testing during an emergency department visit, while 144 were tested as inpatients (17%). Physicians performed the D-dimer test to evaluate DVT and PE in 238 (28%) and 625 (72%) patients, respectively. Overall, the testing strategy was appropriate in 69% (95% confidence interval [CI]: 66%–72%) of cases. The testing strategy was more likely to be appropriate for emergency department versus inpatients (75% vs. 39%, p < 0.05) and for DVT versus PE patients (84% vs. 63%, p < 0.05). Of all inappropriately tested patients, under-utilization of diagnostic imaging was more common than over-utilization (90% vs. 10%, p < 0.05). VTE was confirmed in 37 of 138 ‘DVT patients’ and 35 of 625 ‘PE patients’ (16% [95% CI: 11%–21%] and 6% [95% CI: 4%–8%], respectively). In conclusion, physicians often fail to use diagnostic testing strategies for VTE correctly following a D-dimer test.