bluuebunny/crossref_metadata_2025_split huggingface dataset:
Venous thromboembolism (VTE) in Europe
Authors: Agnelli Giancarlo , Anderson Frederick , Arcelus Juan , Bergqvist David , Brecht Josef , Greer Ian , Heit John , Hutchinson Julia , Kakkar Ajay , Mottier Dominique , Oger Emmanuel , Samama Meyer-Michel , Spannagl Michael , Cohen Alexander ,   for the VTE Impact Assessment Group in Europe (VITAE)
Published: October 2007

SummaryVenous thromboembolism (VTE) is often asymptomatic, misdiagnosed, and unrecognized at death, and there is a lack of routine postmortem examinations. These factors are thought to result in marked underestimates ofVTE incidence. The objective of our study was to estimate the total burden of VTE within the European Union (EU) per annum. An epidemiological model was constructed to estimate the number of community- and hospital-acquired incidents and recurrent cases (attack rate) of nonfatal VTE and VTE-related deaths, as well as incident and prevalent cases of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (PH) occurring in the EU per annum. Individual models were developed for six EU countries. The models were populated with data from published literature and, where necessary, expert opinions. The findings were tested using probabilistic sensitivity analyses. The esti mated total number of symptomaticVTE events (range based on probabilistic sensitivity analysis) per annum within the six EU countries was 465,715 (404,664–538,189) cases of deep-vein thrombosis, 295,982 (242,450–360,363) cases of pulmonary embolism (PE), and 370,012 (300,193–483,108) VTE-related deaths. Of these deaths, an estimated 27,473 (7%) were diagnosed as being antemortem; 126,145 (34%) were sudden fatal PE, and 217,394 (59%) followed undiagnosed PE. Almost threequarters of all VTE-related deaths were from hospital-acquired VTE.VTE is a major health problem in the EU, with over one million VTE events or deaths per annum in the six countries examined. Given the availability of effective VTE prophylaxis, many of these events and deaths could have been prevented. These results have important implications for the allocation of healthcare resources.
Spiral computed tomography for the diagnosis of acute pulmonary embolism
Authors: Kayali Fadi , Hull Russell , Stein Paul 
Published: October 2007

SummaryThe accuracy of computed tomography (CT) imaging for the diagnosis of acute pulmonary embolism (PE) was reviewed. Single detector CT, based on pooled data, showed a sensitivity of 73% and multidetector CT, mostly 4-slice, showed a sensitivity of 83%. Respective specificities were 87% and 96%. Among patients with suspected PE evaluated with single slice CT,20% of patients found to have venous thromboembolic disease were diagnosed on the basis of a positive CT venous phase venogram. With multislice CT, 14% were diagnosed on the basis of a positive CT venogram.The positive likelihood ratio with single detector CT was 5.7 and with multidetector CT it was 19.6. Respective negative likelihood ratios were 0.31 and 0.18. Calculations of post-test probability using pretest probability and likelihood ratios according to Bayes’ theorem showed that even with multidetector CT, false positive and false negative images are not uncommon when clinical assessment is discordant with the CT interpretation. Outcome studies showed recurrent PE in only 1.7% or fewer untreated patients with negative CT pulmonary angiograms.
Food deprivation induces adipose plasminogen activator inhibitor-1 (PAI-1) expression without accumulation of plasma PAI-1 in genetically obese and diabetic db/db mice
Authors: Oishi Katsutaka , Ohkura Naoki , Matsuda Juzo , Ishida Norio 
Published: October 2007

SummaryRelationships between energy intake and fibrinolytic functions have been documented in detail. We evaluated food deprivation (FD) as a means of modulating fibrinolytic activity in genetically obese and diabetic db/db mice and in their lean counterparts. Twelve hours of FD induced considerable gene expression of plasminogen activator inhibitor-1 (PAI-1) in both epididymal (3.8-fold, p<0.05) and intestinal (2.4-fold, p<0.05) adipose tissues without affecting plasma PAI-1 levels in db/db mice, whereas the FD did not affect these parameters in wild-type mice. Importantly, 24 hours of FD increased the plasma PAI-1 content in wild-type (1.9-fold, p<0.01) but not in db/db mice, although adipose PAI-1 mRNA levels were significantly increased in db/db mice. The plasma PAI-1 content significantly correlated with hepatic PAI-1 mRNA levels in wild-type (r=0.84, p<0.01) and in db/db (r=0.63, p<0.01) mice. However, plasma PAI-1 did not correlate with adipose PAI-1 expression in db/db mice, although adipose tissue in general is thought to be the principal site of PAI-1 production in obesity. Hepatic PAI-1 expression was closely correlated with serum levels of free fatty acids in wild-type (r=0.72, p<0.01), but not in db/db mice. Adipose PAI-1 expression significantly correlated with serum corticosterone levels in both genotypes (wild-type, r=0.52, p<0.05; db/db, r=0.51, p<0.01), suggesting that adipose PAI-1 expression is up-regulated by fastinginduced glucocorticoids. The present findings suggested that fasting differentially affects fibrinolytic activity in obese and lean subjects and that PAI-1 expression in the liver as well as in adipose tissues comprises an important determinant of increased risk for cardiovascular disease in obesity.
Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c
Authors: van de Poel Marlène , Coppens Michiel , Hamulyák Karly , Prins Martin , van der Meer Jan , Veeger Nic , Büller Harry , Middeldorp Saskia , Bank Ivan 
Published: October 2007

SummaryElevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences ofVTE were 1.25% (0.46–2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03–0.82) in those with normal levels (OR 5.5 [1.1–27.3]). The annual incidences of arterial vascular events were 1.04% (0.34–2.42) and 0.23% (0.03–0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9–23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1–13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.
Urotensin-II in the lung: A matter for vascular remodelling and pulmonary hypertension?
Authors: Djordjevic Talija , Görlach Agnes 
Published: October 2007

SummaryUrotensin-II (UII) is an evolutionary conserved peptide which has been initially discovered in the urophysis of the fish goby regulating body fluid composition and vascular tone. Mammalian UII has gained increasing interest since it has been considered as an even more potent vasoconstrictor than endothelin-1, although its efficiency is greatly variable throughout species and vascular beds. More recently, it has been shown that UII, which mediates its action via binding to the G-protein coupled urotensin-II receptor, is not only involved in the regulation of the vascular tone but can also stimulate a variety of signaling cascades in different cells and organs in the body including generation of reactive oxygen species and nitric oxide, activation of MAP kinases, and modulation of gene expression. Indeed, UII can stimulate proliferative processes, affect the extracellular matrix and may even add to a prothrombotic state. Such vascular remodelling processes are, in conjunction with enhanced vasoconstriction, involved in the pathogenesis of pulmonary hypertension, suggesting that UII may play a novel role in the pathogenesis of this disorder.
ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome
Authors: Frere Corinne , Cuisset Thomas , Quilici Jacques , Camoin Laurence , Carvajal Joseph , Morange Pierre Emmanuel , Lambert Marc , Juhan-Vague Irène , Bonnet Jean-Louis , Alessi Marie-Christine 
Published: October 2007

SummaryClopidogrel responsiveness has been proposed to be involved in recurrent ischemic events after stenting for non-ST elevation acute coronary syndromes (NSTE ACS). However, its biological definition is not consensual. We assess the value ofADP-induced platelet aggregation (ADP-Ag) and platelet reactivity indexVASP (PRI VASP) in predicting recurrent ischemic events in patients with NSTE ACS undergoing percutaneous coronary intervention (PCI). We studied 195 consecutive NSTE ACS patients undergoing PCI after a 600 mg loading dose of clopidogrel. ADPAg and PRI VASP were analysed. The primary end-point was recurrent ischemic events within 30 days of PCI. It occurred in 14 patients (7%). Construction of ROC curves to examine the value of predictive models showed that sensitivity and specificity for primary endpoint were 79% and 76%, respectively, for a maximal intensity of ADP-Ag ≥70%, 93% and 50% for PRIVASP> 53%. The positive and negative predictive values were 21% and 98%, respectively, for ADP-Ag ≥70%, 12% and 99% for PRIVASP> 53%. In patients with NSTE ACS undergoing PCI, ADP-Ag and PRI VASP identify low responders to clopidogrel with an increased risk of recurrent ischemic events with respective cut-off values of 70% and 53%.
The risk of bleeding with warfarin: A systematic review and performance analysis of clinical prediction rules
Authors: Dahri Karen , Loewen Peter 
Published: October 2007

SummaryIt was the objective of this article to qualitatively review and evaluate the clinical prediction rules (CPRs) available for estimating bleeding risk in patients commencing warfarin therapy. A systematic review of PubMed (1949 to December 2006), MEDLINE (1966 to December 2006); EMBASE (1980 to December 2006), Cochrane Database of Systematic Reviews (to December 2006), and International Pharmaceutical Abstracts (1970 to Demember 2006) was conducted. Seven studies were found that detailed CPRs used to assess risk of bleeding prior to commencing warfarin therapy. Four studies described distinct CPRs. The remaining three studies were further validations of one of the CPRs, the Outpatient Bleeding Risk Index. The Outpatient Bleeding Risk Index was classified as being of Level 2 evidence while the remaining three indices were classified as being of Level 4 evidence. In no case did the CPRs exhibit performance characteristics that would indicate“strong” ability to predict the presence of absence of major bleeding among warfarin recipients. The modified Outpatient Bleeding Risk Index exhibited moderate predictive ability for major bleeding in two studies, although pooling of all studies of this CPR did not reveal moderate or better performance. None of the CPRs identified “any bleeding” with moderate or strong predictive ability. None of the available CPRs exhibit sufficient predictive accuracy or have trials evaluating the impact of their use on patient outcomes. Hence, no existing CPR can be recommended for widespread use in practice at present.
Low protein Z levels in patients with peripheral arterial disease
Authors: Cesari Francesca , Pratesi Giovanni , Cellai Anna Paola , Pulli Raffaele , Pratesi Carlo , Gensini Gian Franco , Abbate Rosanna , Fedi Sandra , Sofi Francesco 
Published: October 2007

SummaryConflicting findings regarding the association between protein Z and atherosclerotic disease have been reported. The aim of this case-control study was to evaluate the role of protein Z in a peripheral localization of atherosclerosis. We studied protein Z levels in 120 patients (102 male, 18 female; median age: 75 years) admitted to the Unit of Vascular Surgery of the University of Florence with a clinical manifestation of peripheral arterial disease (PAD), and in 360 healthy subjects selected to be comparable to the patients group in terms of age and gender. Protein Z levels were found to be significantly (p < 0.05) lower in PAD patients [1,594 (89–3,635) ng/ml] compared to the healthy control group [1,728 (300–3,736) ng/ml].A logistic regression analysis showed, at univariate analysis, a significantly increased risk of PAD in patients with low levels of protein Z (<5th percentile of our control group: < 601 ng/ml) (OR: 5.72, 95%CI 3.07–10.66; p < 0.0001). After adjustment for age, gender and traditional cardiovascular risk factors the association was confirmed (OR: 5.83, 95%CI 2.83–12.01; p < 0.0001). Moreover, a significant association between low protein Z levels and clinical severity of the disease, evaluated through Fontaine’s stages, was reported after adjustment for age, gender, and traditional cardiovascular risk factors (general linear model, p for trend: 0.03). In conclusion, our data shows an association between low protein Z levels and the occurrence of PAD. These findings provide evidence for the role of protein Z in the pathogenesis of the atherosclerotic disease.
Blood coagulation at the site of microvascular injury in healthy and coumadin-treated subjects heterogenous for factor V Leiden mutation
Authors: Undas Anetta , Brzezinska-Kolarz Beata , Orfeo Tom , Brummel-Ziedins Kathleen , Musial Jacek , Szczeklik Andrew , Mann Kenneth 
Published: October 2007

SummaryThere is little knowledge regarding the in-vivo course of coagulation reactions in subjects with factor (F)V Leiden (G1691A, R506Q). The aim of the current study was to evaluate the effect of FV Leiden on coagulant reactions triggered by vascular injury. At the site of microvascular injury, prothrombin activation and FVa formation and inactivation have been evaluated in 16 apparently healthy subjects and 16 patients on long-term anticoagulation with acenocoumarol, with eight heterogenous carriers of FV Leiden in the healthy and in the anticoagulated group. Thrombin formation, measured by levels of thrombin-antithrombin complexes (TAT) and thrombin B-chain, proceeded at similar rates in the bleeding-time blood in carriers and non-carriers of FV Leiden. The onset and rate of FV activation did not differ significantly among the four groups. When healthy carriers of FV Leiden were compared to healthy non-carriers, the onset of FVa inactivation by activated protein C (APC) was delayed by 60 to 90 seconds (p=0.01). Anticoagulated individuals also showed the same pattern of FV Leiden associated differences in the time of occurrence of the 30 kD FVa heavy-chain fragment (p=0.021). Our results indicate that when blood clotting is triggered by microvascular injury, the heterozygous expression of FV Leiden has no effect on thrombin generation in healthy or coumadintreated subjects. Inactivation of FVa by theAPC mechanism is attenuated significantly in carriers of FV Leiden but the magnitude of this effect is smaller than that observed in most purified systems.
New functional aspects of the L-arginine-nitric oxide metabolism within the circulating blood
Authors: Keymel Stefanie , Kelm Malte , Kleinbongard Petra 
Published: October 2007

SummaryNitric oxide (NO) is a signaling molecule of major importance modulating not only the function of the vascular wall but also that of blood cells, such as platelets and leukocytes. The synthesis of NO in the circulation has been attributed mainly to the vascular endothelium. Red blood cells (RBC) have been demonstrated to carry a non-functional NOS and – due to their huge haemoglobin content – have been assumed to metabolize large quantities of NO. More recently, however, RBC have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We provide evidence that RBC from humans express an active and functional endothelial type NOS. RBC NOS activity may regulate deformability of RBC, and inhibits activation of platelets. This review aims to discuss the potential role of RBC NOS in the circulation and new concepts of NO research in the microcirculation.
Factor V Leiden mutation is associated with enhanced arterial thrombotic tendency in lean but not in obese mice
Authors: Nagai Nobuo , Cleuren Audrey , Rosendaal Frits , Van Hoef Berthe , Hoylaerts Marc , Van Vlijmen Bart , Lijnen Roger 
Published: October 2007

SummaryThe homozygous factorV Leiden mutation is associated with enhanced venous thrombotic risk. Obesity is a major risk factor for development of thrombotic cardiovascular disease. It was the objective of this study to investigate whether obesity affects the thrombotic risk associated with the mutation. Male mice with homozygous factor V Leiden mutation (Arg 504 to Gln) (FVQ/Q) and corresponding wild-type (WT) mice were kept on a standard fat diet (SFD) or high fat diet (HFD) for 14 weeks, and femoral artery thrombosis was induced by FeCl3 treatment. As compared to SFD, HFD feeding for 14 weeks resulted in significantly higher body weight and fat mass associated with adipocyte hypertrophy, which were, however, similar for both geno types. In the FeCl3-induced arterial thrombosis model, FVQ/Q mice kept on SFD had a 40% shorter occlusion time (p = 0.015) and 40% lower blood flow (p = 0.03), as compared to WT mice. However, on HFD the occlusion time and blood flow were not significantly different for both genotypes. This finding could not be explained by differential changes of coagulation factors in either genotype fed on SFD or HFD. In conclusion, on SFD, but not on HFD, the factorV Leiden mutation is associated with enhanced thrombotic tendency after FeCl3 injury of the femoral artery, suggesting that in this model obesity rescues the increased thrombotic risk associated with the factorV Leiden mutation.
Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber
Authors: Zafar Mohammad Urooj , Vorchheimer David , Gaztanaga Juan , Velez Mauricio , Yadegar Daniel , Moreno Pedro , Kunitada Satoshi , Pagan Juan , Fuster Valentin , Badimon Juan 
Published: October 2007

SummaryDirect and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n=12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p<0.05). Under arterial condition, the reduction was 26% and 17% (p<0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2=0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.
Potential implications of vascular wall resident endothelial progenitor cells
Authors: Tilki Derya , Hohn Hans-Peter , Gehling Ursula , Kilic Nerbil , Ergün Süleyman 
Published: October 2007

SummaryA rapidly increasing body of data suggests an essential role of endothelial progenitor cells (EPCs) in vascular regeneration, formation of new vessels in cardiovascular diseases and also in tumor vasculogenesis. Moreover, recent data obtained from clinical studies with anti-angiogenic drugs in tumor therapy or with pro-angiogenic stimuli in ischemic disorders implicate a predictive role of the number of EPCs circulating in the peripheral blood in monitoring of these diseases. However, there is still some controversial data regarding the relevance of the EPCs in vascular formation depending on models used and diseases studied. One of the essential prerequisites for a better understanding of the whole contribution of EPCs to vascular formation in adult, a process called postnatal vasculogenesis, is to identify their exact sources. We could recently discover the existence of EPCs in a distinct zone of the vascular wall of large and middle sized adult blood vessels and showed that these cells are capable to differentiate into mature endothelial cells, to form capillary sprouts in arterial ring assay and to build vasa vasorumlike structures within the vascular wall. They also can be mobilized very rapidly from the vascular wall by tumor cells. This review will discuss the functional implications of these vascular wall resident endothelial progenitor cells (VW-EPCs) in relation to those of EPCs circulating in peripheral blood or derived from the bone marrow in cardiovascular and neoplastic diseases.
Factor Xa-driven thrombin generation in plasma: Dependency on the aminophospholipid density of membranes and inhibition by phospholipid-binding proteins
Authors: Wielders Simone , Ungethüm Lisette , Reutelingsperger Chris , Bevers Edouard , Lindhout Theo 
Published: October 2007

SummaryPhosphatidylserine (PS) externalization of activated platelets plays a pivotal role in haemostasis and thrombosis. In the present study we have explored the relationship between the PS density of membranes and the rate of thrombin generation in plasma. Factor (F)Xa-initiated thrombin generation was measured in platelet-free plasma (PFP) containing either phospholipid vesicles of varying PS-content or non-stimulated platelets (reconstituted PRP). The duration of the initiation phase of FXa-driven thrombin generation decreased dramatically with increasing PS density. Concomitantly, the maximal rate of thrombin generation during the propagation phase (maxR) increased non-linearly, with the steepest incline between 5 and 10 mol% PS. Titration of FVa into plasma containing 2 mol% PS increased maxR proportionally and diminished the lag phase. In contrast, platelet-dependent thrombin generation was not influenced by addition of FVa. With increasing platelet concentration, the duration of the initiation phase drastically decreased, and maxR increased proportionally. At a physiologically relevant platelet concentration, maxR corresponded with the maxR found with 2 µM of 10 mol% PS. Annexin A5 (AnxA5) and lactadherin appeared to be powerful inhibitors of in-situ thrombin generation under all conditions examined, with AnxA5 being three- to fourfold more potent than lactadherin. In conclusion, maximal thrombin generation in plasma requires membranes with a density of 10–20 mol% PS. Our data further indicate that thrombin formed in situ induces externalization of PS to approx 10 mol% in a substantial platelet subpopulation.