bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis C in Hemodialysis Patients: Current Global Magnitude, Natural History, Diagnostic Difficulties, and Preventive Measures
Authors: Rahnavardi Mohammad , Hosseini Moghaddam Seyed Mohammadmehdi , Alavian Seyed Moayed
Published: February 2008

Hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality in hemodialysis (HD) patients. The reported prevalence of HCV among the HD population has varied greatly from 1.9 to 84.6% in different countries in recent years. The length of time on HD is generally believed to be associated with HCV acquisition in HD subjects. Nevertheless, several recent reports failed to recognize any significant role of blood transfusion. Although there are some considerations about the accuracy of serologic testing in detecting HCV in HD patients, the accumulated data in this review suggest the false-negativity rate to be not more than 1.66% (153/9,220). Therefore, substituting virologic for serologic testing in the routine diagnosis of HCV infection in HD patients seems unreasonable. Several phylogenetic analyzes of viral isolates suggested nosocomial patient-to-patient transmission of HCV among HD patients for which the main potential source is believed to be contaminated hands and articles. However, isolation of HCV-infected HD patients and use of dedicated machines are currently unjustified while strict adherence to universal precautions seems to be enough to control disease spread in HD units. The present article is an update on epidemiological and clinical features of HCV in HD population.
Cognitive Status in Hypothyroid Female Patients: Event-Related Evoked Potential Study
Authors: Anjana Y. , Tandon O.P. , Vaney N. , Madhu S.V.
Published: February 2008

Aim:Higher brain functions are adversely affected in hypothyroid patients. The central nervous system features of hypothyroidism include mental retardation, various cognitive and memory deficits that have been evaluated by different neuropsychological tests. In the present study event-related potentials (ERPs) have been used to assess the cognitive status of hypothyroid patients before and after treatment. Methods: Twenty-six newly diagnosed hypothyroid female patients with a mean age of 31.85 ± 8.57 years and 26 female controls with a mean age of 30.92 ± 7.24 years were the subjects of the study. The ERPs were recorded on a computerized evoked potential recorder using the 10–20 system of electrode placement and the standard auditory ‘oddball’ paradigm. The first recording of ERPs was done at the time of diagnosis and the second recording was done 3 months after the start of treatment in a euthyroid state. Results: Prolongation of latencies was found in the early ERP components (N100, P200 and N200) in hypothyroid patients compared to controls, while no significant group differences were found on P300. In the hypothyroid group all the ERP latencies decreased significantly after attainment of euthyroidism compared to pretreatment values. ERP amplitudes revealed no significant group differences between hypothyroid patients and controls, but significant amplitude increases were found on the waves of N200 and P300 after treatment compared with pretreatment values in the hypothyroid group. Conclusions: Hypothyroid patients showed prolongation of latencies only in the early ERP components compared to controls. In hypothyroid patients, ERP findings indicate a speeding of sensory and cognitive processing in a state of euthyroidism compared to the pretreatment condition.
Effect of an anti-sulfatide single-chain antibody probe on platelet function
Authors: Shrimpton Corie , Honke Koichi , Rumbaut Rolando , Lopez Jose , Thiagarajan Perumal , Guchhait Prasenjit
Published: February 2008

Sulfatide (galactocylceramide-3'-sulfate), a cell surface glycosphingolipid interacts with several cell adhesion molecules including fibrinogen, von Willebrand factor (VWF), P-selectin, thrombospondin (TSP) and laminin, which are involved in haemostasis.We have used a sulfatide-specific single-chain fragment variable (scFv) antibody probe PA38 and sulfatide-deficient mice to investigate the role of membrane sulfatide in platelet function. PA38 bound to platelets and binding increased following platelet activation. Sulfatide was localized as a large cluster towards the center of the platelet surface when examined in a confocal microscope. PA38 (20 μg/ml) inhibited the adhesion of activated platelets to fibrinogen,VWF, P-selectin,TSP1 and laminin by 30%, 30%,75%,20% and 35%,respectively,compared to a control scFv (p<0.05). Furthermore, PA38 inhibited collagen, ADP, thrombin and ristocetin-induced platelet aggregation in PRP by 25%, 30%, 18% and 20%, respectively, compared to the control scFv (p<0.05). In a PFA-100 platelet function assay, PA38 prolonged the occlusion time by 25% (p<0.05).Under flow PA38 decreased the thrombus formation on collagen by 31%, (p<0.01). Sulfatidedeficient mice displayed an extended lag-phase in collagen-induced platelet aggregation compared to wild type (p<0.05), though in-vivo haemostasis did not differ significantly.Thus, this study provides new evidence for a role for membrane sulfatide in platelet function.
C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor α, on human monocytes
Authors: Ropars Armelle , Seguin-Devaux Carole , Poitevin Gaël , Grosjean Sandrine , Latger-Cannard Vèronique , Devaux Yvan , Zannad Faiez , Regnault Vèronique , Lacolley Patrick , Mertes Paul-Michel , Hanriot Didier , Bello Gaëlle , Hess Ketsia , Longrois Dan
Published: February 2008

Non-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated.We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n=9/group) were exposed to purified CRP (25 μg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1α, IL-1β and IL-6, and the chemokines GRO-α, GRO-β and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) α and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRα mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRα protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRα. Western Blot analysis revealed CRP-induced nuclear translocation of NF-κB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRá mRNA expression was inhibited by anti-CD64 (FcγRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRα pathway.
Concentration-dependent roles for heparin in modifying liopolysaccharide-induced activation of mononuclear cells in whole blood
Authors: Hochart Helene , Jenkins Vincent , Preston Roger , Smith Owen , White Barry , O’Donnell James
Published: February 2008

In addition to their anticoagulant activity,unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have important immunomodulatory properties. However, different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear.It was the objective of this study to determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide- binding protein (LBP) in mediating this effect. Whole blood was pre-treated with UFH or LMWH (0.1–200 IU/ml), prior to stimulation with LPS (10 ng/ml). After six hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1β, IL-6, IL-8, and TNF-α) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of LBP (50–100 nM). Under serum-free conditions, heparin demonstrated dose-dependent anti-inflammatory effects,significantly reducing secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) in response to LPSstimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1β and IL-8 following LPS-stimulation) of heparin were also observed,but only at supra-therapeutic doses (10–200 IU/ml). Our data demonstrate that in the absence of LBP, the direct effect of heparin on LPS-stimulated monocytes is anti-inflammatory. However in whole blood, the immunomodulatory effects of heparin are significantly more complex, with either pro- or anti-inflammatory effects dependent upon heparin concentration.
Selective inhibition of the platelet phosphoinositide 3-kinase p110β as promising new strategy for platelet protection during extracorporeal circulation
Authors: Wendel Hans , Dietz Klaus , Schiebold Daniela , Peter Karlheinz , Schoenwaelder Simone , Ziemer Gerhard , Straub Andreas
Published: February 2008

Extracorporeal circulation (ECC) is used in cardiac surgery for cardiopulmonary bypass as well as in ventricular assist devices and for extracorporeal membrane oxygenation. Blood contact with the artificial surface and shear stress of ECC activates platelets and leukocytes resulting in a coagulopathy and proinflammatory events. Blockers of the platelet glycoprotein (GP) IIb/IIIa (CD41/CD61) can protect platelet function during ECC, a phenomenon called “platelet anaesthesia”, but may be involved in post-ECC bleeding. We hypothesized that the new selective phosphoinositide 3-kinase p110β inhibitor TGX-221 that inhibits shear-induced platelet activation without prolonging the bleeding time in vivo may also protect platelet function during ECC. Heparinized blood of healthy volunteers (n=6) was treated in vitro with either the GP IIb/IIIa blocker tirofiban, TGX-221 or as control and circulated in an ECC moand after 30 minutes circulation CD41 expression on the ECCtubing as measure for platelet-ECC binding and generation of the platelet activation marker β-thromboglobulin were determined using ELISA. Platelet aggregation and platelet-granulocyte binding were analysed in flow cytometry. After log-transforming the data statistical evaluation was performed using multifactor ANOVA in combination with Tukey’s HSD test (global alpha = 5%).Tirofiban and TGX-221 inhibited platelet-ECC interaction, platelet aggregation and platelet-granulocyte binding. Tirofiban also inhibited ECC-induced β-thromboglobulin release.The observed inhibition of platelet-ECC interaction and platelet activation by tirofiban contributes to explain the mechanism of“platelet anaesthesia”.TGX-221 represents a promising alternative to GP IIb/IIIa blockade and should be further investigated for use during ECC in vivo.
The C242T polymorphism of the p22phox component of NAD (P)H oxidase and vascular risk
Authors: Castelnuovo Augusto , Soccio Manola , Iacoviello Licia , Evangelista Virgilio , Consoli Agostino , Vanuzzo Diego , Diviacco Silvia , Carluccio Marisa , Caterina Raffaele , Rignanese Lucia
Published: February 2008

NAD(P)H oxidase is a prominent source of reactive oxygen species in the vasculature.Vascular NAD(P)H oxidase is comprised of several subunits, one of which, p22phox, is encoded by a gene exhibiting several allelic variants. Here the C242T nucleotide transition has been found to alter superoxide anion production and associated with an altered risk of coronary artery disease (CAD). We assessed the role of this variant in two casecontrol studies, and performed a meta-analysis of previously reported investigations relating it to vascular risk. Population I was comprised of 492 subjects with type 2 diabetes, with or without macrovascular disease,matched for age,sex,and duration of diabetes. Population II was comprised of 158 subjects with or without either CAD or cerebro-vascular disease, and matched for age,sex,smoking status,weight category and the presence of hypertension, dyslipidemia, and diabetes. Our findings were metaanalyzed together with additional studies retrieved from the literature. The C242T polymorphism distribution did not differ between cases and controls in populations I and II both at univariate and multivariate analyses, and this was confirmed in a metaanalysis with || previously published populations. The metaanalysis, however, suggested a protective role of the T allele on CAD as an end point in Asian populations. In conclusion, these data suggest a significant heterogeneity for a modulating role of the T allele in the C242T polymorphism of p22-phox for the occurrence of CAD across ethnicities,with the absence of a significant effect in Caucasians.
Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations
Authors: Tait R. , Shaffer Don , Baudo Francesco , Boneu Bernard , Dempfle Carl , Horellou Marie , Klamroth Robert , Lazarchick John , Mumford Andrew , Schulman Sam , Shiach Caroline , Bonfiglio Laura , Frieling Johan , Conard Jacqueline , Depka Mario , Tiede Andreas
Published: February 2008

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis,and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditaryAT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days.No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.
Increased thrombin generation in persons with echogenic carotid plaques
Authors: Mathiesen Ellisiv , Østerud Bjarne , Amiral Jean , Vissac Anne , Hansen John-Bjarne , Notø Ann-Trude
Published: February 2008

Echolucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis.Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The present study was conducted to investigate the influence of plaque morphology on thrombin generation in persons with carotid stenosis. One hundred twenty-eight persons with carotid stenosis (≥35% lumen diameter reduction) and 136 matched controls without stenosis were recruited from the health survey of the Tromsø Study. Blood samples were collected and plaque morphology determined by ultrasonography. Thrombin generation was assessed by thrombin-antithrombin complexes (TAT) and by prothrombin fragment 1+2 (F1+2).Persons with echogenic plaques (n=63) had significantly higher levels of TAT (5.24 μg/l, 4.33–6.14) (mean, 95%CI) than persons with echolucent plaques (n=65) (3.44 μg/l, 2.91–3.96, p<0.001) and controls (n=136) (3.33 μg/l, 3.06–3.60, p<0.001).They also had significantly higher levels of F1+2 (2.14 nM, 1.83–2.45) than persons with echolucent plaques (1.54 nM, 1.38–1.71, p<0.001) and controls (1.49 nM, 1.40–1.58, p<0.001). TAT and F1+2 increased linearly with plaque echogenicity (p=0.002 and p=0.001, respectively) independent of the degree of stenosis. Increased thrombin generation was associated with a significant increase in plasma factorV levels among persons with echogenic plaques compared to echolucent plaques (p=0.049) and controls (p=0.025). The present findings indicate that increasing plaque echogenicity, rather than plaque echolucency and the degree of stenosis, is associated with thrombin generation in persons with carotid stenosis.
Treatment of pulmonary embolism: The use of low-molecularweight heparin in the inpatient and outpatient settings
Authors: Hull Russell
Published: February 2008

Pulmonary embolism (PE) remains a major clinical problem associated with considerable mortality and morbidity. In patients with PE, appropriate anticoagulant therapy has been shown to significantly reduce both recurrence and mortality. Low-molecular- weight heparin (LMWH) is at least as effective as unfractionated heparin (UFH) in the treatment of PE,with a similar risk of bleeding. Furthermore, LMWH offers more predictable pharmacokinetics and anticoagulant effects. As a result, current guidelines from both the American College of Chest Physicians and the joint American College of Physicians/American Academy of Family Physicians recommend the use of LMWH over UFH (in patients with submassive PE). Outpatient treatment with LMWH has been shown to be feasible in many patients,and offers the potential for cost-savings and improvements in healthrelated quality of life. Further data are needed to support an evidence- based recommendation for the use of LMWH in the outpatient treatment of PE.
The interaction of fragment 1 of prothrombin with the membrane surface is a prerequisite for optimum expression of factor Va cofactor activity within prothrombinase
Authors: Bukys Michael , Orban Tivadar , Kim Paul , Nesheim Michael , Kalafatis Michael
Published: February 2008

Incorporation of factor (F) Va into prothrombinase directs prothrombin activation by FXa through the meizothrombin pathway, characterized by initial cleavage at Arg320 We have shown that a pentapeptide with the sequence DYDYQ specifically inhibits this pathway. It has been also established that Hir54–65(SO3 -) is a specific inhibitor of prothrombinase.To understand the role of FVa within prothrombinase at the molecular level, we have studied thrombin formation by prothrombinase in the presence of various prothrombin-derived fragments alone or in combination. Activation of prethrombin 1 is slow with cleavages at Arg320 and Arg271 occurring with similar rates. Addition of purified fragment 1 to prethrombin 1 accelerates both the rate of cleavage at Arg320 and thrombin formation.Both reactions were inhibited by Hir54–65(SO3 -) while DYDYQ had no significant inhibitory effect on prethrombin 1 cleavage in the absence or presence of fragment 1. Similarly, activation of prethrombin 2 by prothrombinase,is inhibited by Hir54–65(SO3 -), but is not affected by DYDYQ.Addition of purified fragment 1•2 to prethrombin 2 accelerates the rate of cleavage at Arg320 by prothrombinase. This addition also results in a significant inhibition of thrombin formation by DYDYQ and is concurrent with the elimination of the inhibitory effect of Hir54–65(SO3 -) on the same reaction. Finally, a membrane-bound ternary complex composed of prethrombin 2/fragment 1•2/Hir54–65(SO3 -) is inhibited by DYDYQ. Altogether,the data demonstrate that membrane- bound fragment 1 is required to promote optimum FVa cofactor activity which in turn is translated by efficient initial cleavage of prothrombin by prothrombinase at Arg320.
Evaluation of a venous-return assist device to treat severe post-thrombotic syndrome (VENOPTS)
Authors: McRae Simon , Kahn Susan , Julian Jim , Kearon Clive , MacKinnon Betsy , Magier Debbie , Strulovich Carla , Lyons Theresa , Robinson Sandra , Hirsh Jack , Ginsberg Jeffrey , O’Donnell Martin
Published: February 2008

Severe post-thrombotic syndrome (PTS) is responsible for considerable disability, reduced quality of life and increased health care costs. Current therapies are limited and often ineffective. We performed a two-centre,randomized,cross-over controlled trial to evaluate Venowave
TM, a novel lower-limb venous-return assist device, for the treatment of severe PTS. Eligible subjects were allocated to receive, in randomized order, Venowave for eight weeks and a control device for eight weeks. The eightweek treatment periods were separated by a four-week period when no device was used (i.e. wash-out period). The primary outcome measure was a ‘clinical success’ defined as: i) reported benefit from the device; and ii) moderate or greater improvement in symptoms of PTS; and iii) willingness to continue using the device. Secondary outcome measures included quality of life (QOL) as measured by VEINES-QOL questionnaire (higher scores indicate better QOL), and PTS severity as measured by the Villalta PTS scale (higher scores indicate more severe PTS). The study was registered with ClinicalTrials.gov (NCT00182208). Thirty-two patients were enrolled. Of these, 26 (80%) were also using graduated compression stockings. Twenty-six participants completed both trial periods. Clinical success occurred in 10 (31%) participants receiving Venowave and four (13%) participants receiving the control device, with two (6%) participants reporting a clinical success with both devices (P=0.11). Mean VEINES-QOL score at the end of study period was significantly greater (P=0.004) forVenowave (52.5; SD 5.8) compared to control (50.2;SD 6.2).MeanVillalta scale score at the end of study period was significantly decreased (P=0.004) for Venowave (12.2; SD 6.3) compared to control (15.0; SD 6.1). In conclusion,Venowave appears to be a very promising new therapy for patients with severe PTS, which may be used alone or in combination with graduated compression stockings.
Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities
Authors: Fonseca Roberto , Oliveira Stephan-Nicollas , Melo Fábio , Pereira Maria , Benevides Norma , Mourão Paulo
Published: February 2008

We compared sulfated galactans (SGs) from two species of red algae using specific coagulation assays and experimental models of thrombosis.These polysaccharides have an identical saccharide structure and the same size chain, but with slight differences in their sulfation patterns.As a consequence of these differences, the two SGs differ in their anticoagulant and venous antithrombotic activities.SG from G.crinale exhibits procoagulant and prothrombotic effects in low doses (up to 1.0 mg/kg body weight), but in high doses (>1.0 mg/kg) this polysaccharide inhibits both venous and arterial thrombosis in rats and prolongs ex-vivo recalcification time. In contrast, SG from B. occidentalis is a very potent anticoagulant and antithrombotic compound in low doses (up to 0.5 mg/kg body weight), inhibiting venous experimental thrombosis and prolonging ex-vivo recalcification time, but these effects are reverted in high doses. Only at high doses (>1.0 mg/kg) the SG from B. occidentalis inhibits arterial thrombosis. As with heparin, SG from G. crinale does not activate factor XII, while the polysaccharide from B. occidentalis activates factor XII in high concentrations, which could account for its procoagulant effect at high doses on rats. Both SGs do not modify bleeding time in rats.These results indicate that slight differences in the proportions and/or distribution of sulfated residues along the galactan chain may be critical for the interaction between proteases, inhibitors and activators of the coagulation system, resulting in a distinct pattern in anti- and procoagulant activities and in the antithrombotic action.
Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry
Authors: Arcelus Juan , Caprini Joseph , Guisado Javier , Soto Mª , Núñez Manuel , Alvárez Juan , Monreal Manuel ,   the RIETE investigators
Published: February 2008

There is little literature about the clinical presentation and timecourse of postoperative venous thromboembolism (VTE) in different surgical procedures. RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic acuteVTE.In this analysis,we analysed the baseline characteristics, thromboprophylaxis and therapeutic patterns, timecourse, and three-month outcome of all patients with postoperative VTE. As of January 2006, there were 1,602 patients with postoperativeVTE in RIETE: 393 (25%) after major orthopaedic surgery (145 elective hip arthroplasty, 126 knee arthroplasty, 122 hip fracture); 207 (13%) after cancer surgery; 1,002 (63%) after other procedures. The percentage of patients presenting with clinically overt pulmonary embolism (PE) (48%, 48%, and 50% respectively), the average time elapsed from surgery toVTE (22 ± 16, 24 ± 16, and 21 ± 15 days, respectively), and the three- month incidence of fatal PE (1.3%, 1.4%, and 0.8%, respectively), fatal bleeding (0.8%, 1.0%, and 0.2%, respectively), or major bleeding (2.3%, 2.9%, and 2.8%, respectively) were similar in the three groups. However, the percentage of patients who had received thromboprophylaxis (96%, 76% and 52%, respectively), the duration of prophylaxis (17 ± 9.6, 13 ± 8.9, and 12 ± 11 days, respectively) and the mean daily doses of low-molecular-weight heparin (4,252 ± 1,016, 3,260 ± 1,141, and 3,769 ± 1,650 IU, respectively), were significantly lower in those undergoing cancer surgery or other procedures. In conclusion, the clinical presentation, time-course, and three-month outcome ofVTE was similar among the different subgroups of patients,but the use of prophylaxis in patients undergoing cancer surgery or other procedures was suboptimal.
Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins
Authors: Provençal Mathieu , Michaud Marisol , Beaulieu Édith , Ratel David , Rivard Georges-Étienne , Gingras Denis , Béliveau Richard
Published: February 2008

Tissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor that is mainly known for its inhibition of tissue factor-mediated coagulation. In addition to its anticoagulant properties, emerging data show that TFPI may also regulate endothelial cell functions via a non-haemostatic pathway. In this work we demonstrate that at concentrations within the physiological range,TFPI inhibits both endothelial cell migration and their differentiation into capillary-like structures in vitro. These effects were specific to endothelial cells since no inhibitory effect was observed on the migration of tumor (glio- blastoma) cells. Inhibition of endothelial cell migration was correlated with a concomitant loss in cell adhesion,suggesting an alteration of focal adhesion complex integrity. Accordingly,we observed thatTFPI inhibited the phosphorylation of focal adhesion kinase and paxillin,two key proteins involved in the scaffolding of these complexes, and that this effect was specific to endothelial cells. These results suggest that TFPI influences the angiogenic process via a non-haemostatic pathway, by downregulating the migratory mechanisms of endothelial cells.
An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases
Authors: Melo Fábio , Mourão Paulo
Published: February 2008

Sulfated galactan from the red alga Botryocladia occidentalis has a potent anticoagulant activity,due to its ability to enhance thrombin and factor Xa inhibition by antithrombin and/or heparin cofactor II. It is less active than unfractionated heparin in arterial thrombosis,but in a venous thrombosis presents a dual effect,inhibiting thrombosis in low but not in high doses.This dual effect on venous thrombosis is a consequence of two actions, one that inhibits thrombin and factor Xa and one that induces factor XII activation. In order to dissociate these effects, we prepared derivatives of the sulfated galactan with low molecular weights. Two fractions that were similar in size to unfractionated heparin and low-molecular-weight heparin were obtained. As the molec- ular weight decreased, the ability to activate factor XII and to promote inhibition of coagulation proteases in the presence of antithrombin and heparin cofactor II diminished.At ∼5 kDa, the sulfated galactan fragment had no effect on factor XII activation, and showed the same effect as unfractionated heparin in a venous thrombosis model.The ∼5-kDa fragment is an antithrombotic with several advantages: i) It is as active as unfractionated heparin in venous thrombosis, but it has little activity in arterial thrombosis; ii) It inhibits venous thrombosis with very little anticoagulant effect; iii) It does not cause bleeding; and iv) It is not obtained from mammals.
Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases
Authors: Jablonska Ewa , Guenther Andreas , Preissner Klaus , Markart Philipp , Wygrecka Malgorzata
Published: February 2008

Acute inflammatory and chronic interstitial lung diseases are characterized by excessive and persistent fibrin deposition in the lung.Intraalveolar fibrin accumulation,observed under these conditions, arises from a leakage of plasma proteins (including fibrinogen) into the alveolar space in combination with a disbalance of alveolar haemostasis. Tissue factor in association with factor VIIa and inhibition of urokinase by plasminogen activator inhibitor-1 are major factors that are responsible for the procoagulant and antifibrinolytic state. In addition, in acute respiratory distress syndrome (ARDS) patients, factor VII-activating protease and extracellular RNA, which may be released into the extracellular milieu from damaged cells during lung injury, may contribute to fibrin formation as well. Fibrin itself can increase vascular permeability, influence the expression of inflammatory mediators and alter the migration and proliferation of various cell types. Additionally, fibrin may inactivate pulmonary surfactant and provide a matrix on which fibroblasts can migrate and produce collagen.Furthermore,cellular activities of haemostatic proteases may also contribute to proinflammatory and fibrotic processes in the lung.The application of coagulation inhibitors, like tissue factor pathway inhibitor, active site-inactivated factor VIIa, activated protein C, antithrombin, heparin or hirudin turned out to be beneficial in experimental models of acute and chronic lung injury. However, the ability of anticoagulant and profibrinolytic agents to improve clinical outcome remains to be elucidated. In the current article, the role of the alveolar coagulation and fibrinolysis systems in acute inflammatory and chronic interstitial lung diseases is discussed with regard to pathomechanisms and modalities of intervention.
P2 receptors, platelet function and pharmacological implications
Authors: Gachet Christian
Published: February 2008

ADP and ATP play a crucial role in platelet activation and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G protein-coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus.Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs like the thienopyridines clopidogrel or prasugrel, or competitive antag-onists such as cangrelor or AZD6140.The optimal inhibition of this receptor to reach clinical efficacy while preserving patients from unacceptable bleeding is a matter of debate. On the other hand, studies in P2Y1 and P2X1 knockout mice and using selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. Finally, the regulation by the P2 receptors of the platelet involvement in inflammatory processes is also briefly discussed.
Individualized antithrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding
Authors: Geisler Tobias , Gawaz Meinrad , May Andreas
Published: February 2008

Dual antiplatelet therapy with aspirin and clopidogrel is currently the standard therapy after coronary stent implantation to prevent a life-threatening stent thrombosis. However, a variety of procedural and individual factors contribute to the individual patient risk and have to be taken into account to allow for an individual recommendation for both the duration and intensity of the antiplatelet therapy. Obviously, the benefit of the prevention of stent thrombosis by antithrombotic therapy has to outweigh the risk of severe bleeding complications. Depending on the individual clinical situation and procedural characteristics (stent type, length, angiographic result etc.), the recommended duration of the combined antiplatelet therapy currently varies from four weeks to at least one year.These recommendations are mainly based on large, prospective, randomized trials and evidence-based guidelines. However, in a subgroup of high-risk patients there is insufficient evidence for the benefit of conventional dual antiplatelet regimen.These include i) patients with an indication for anticoagulation, ii) patients with urgent need for an operation requiring a perioperative withholding of antiplatelet therapy, as well as iii) clopidogrel low responders.This review aims to provide a stratification to define patient collectives who may benefit from more individualized antithrombotic regimens on behalf of currently available literature and guidelines.
Platelet-vessel wall interactions in atherosclerotic disease
Authors: Langer Harald , Gawaz Meinrad
Published: February 2008

During the prolonged course of atherosclerotic disease,platelets are of central importance as they contribute to the initiation of the disease, to its progression and acute exacerbation but also provide potential regenerative mechanisms. Platelets secrete chemokines and cytokines that mediate vascular inflammation and are in turn activated by substances released from cells of the vascular wall.These interactions represent positive and negative feedback loops, which in case of dysregulation may lead to development and progression of disease. Furthermore, platelet adhesion to the endothelium is critical for the initiation of atherosclerotic lesion formation in vivo. Even prior to endothelial denudation, platelet adhesion governed by disturbed flow at predilection sites for atherosclerosis induces recruitment of proathe- rosclerotic cells and release of proinflammatory mediators from all involved cell types.Finally,the pathogenetic role of platelets for late atheroclerotic events including plaque rupture, microembolism or spasms within the microcirculation is well established. However, increasing evidence indicates that platelets mediate on the other hand potential regenerative mechanisms. Platelets recruit circulating progenitor cells to sites of vascular injury. Furthermore, they influence their biological activity and maturation. Therefore,platelets contribute at all stages of vascular disease by interfering with highly dynamic processes. Understanding interactions of platelets with other circulating cells and the vascular wall is a prerequisite to understand cardiovascular disease and to identify potential therapeutic targets.
Magnesium maintains endothelial integrity, up-regulates proteolysis of ultra-large von Willebrand factor, and reduces platelet aggregation under flow conditions
Authors: Cruz Miguel , Aboulfatova Khatira , Martin Cecilia , Choi Hiuwan , Bergeron Angela , Martini Sheryl , Kroll Michael , Kent Thomas , Dong Jing-fei
Published: February 2008

Mg ++ regulates endothelial functions and has anti-inflammatory effects. Its effects on thrombosis have been demonstrated, but the mechanism remains poorly understood.We investigated the roles of MgSO4 in regulating the release and cleavage of the prothrombotic ultra-large (UL) von Willebrand factor (VWF) and VWF-mediated platelet adhesion and aggregation.Washed platelets were perfused over cultured endothelial cells from human umbilical cord veins under a shear stress of 2.5 dyn/cm2. Release and cleavage of ULVWF by ADAMTS-13 was measured in the absence or presence of physiological or therapeutic levels of MgSO4. Whole blood or plasma-free reconstituted blood was perfused over immobilized collagen to measure the effect of MgSO4 on platelet adhesion and aggregation. Also studied were the effects of MgSO4 on ristocetin-induced platelet aggregation andVWF-collagen interaction.Maintenance of endothelial integrity required physiological levels of MgSO4, but exogenous MgSO4 showed no additional benefits.Exogenous MgSO4 significantly enhanced the cleavage of the newly released ULVWF strings by ADAMTS-13 and markedly reduced platelet aggregation on immobilized collagen under flow conditions.This effect is likely to be mediated through VWF as Mg++ partially inhibited ristocetin-induced platelet aggregation andVWF binding to collagen.MgSO4 is critical for maintaining endothelial integrity and regulates ULVWF proteolysis and aggregation under flow conditions. These results provide a new insight into additional mechanisms involved with magnesium therapy.
Platelet GPIb complex as a target for anti-thrombotic drug development
Authors: Clemetson Jeannine , Clemetson Kenneth
Published: February 2008

Specific inhibition of platelet function is a major target of antithrombotic drug research. Platelet receptors are both accessible and specific but have multiple functions often linked to a wide range of ligands. GPIb complex is best known as a major platelet receptor for vonWillebrand factor essential for platelet adhesion under high shear conditions found in arteries and in thrombosis. Recent animal studies have supported inhibition of GPIb as a good candidate for anti-thrombotic drug development with several classes of proteins showing important specific effects and the required discrimination between roles in haemo- stasis and thrombosis is important to protect against bleeding complications.These include antibodies, several classes of snake venom proteins, mutant thrombin molecules and peptides affecting subunit interactions.However,due to the nature of its receptor- ligand interactions involving large protein-protein interfaces, the possibility of developing classic pharmaceutical inhibitors for long term (and perhaps oral) treatment is still unclear, and additional information about structural interactions and signalling mechanisms is essential.
Molecular characterization of two novel mutations causing factor XI deficiency: A splicing defect and a missense mutation responsible for a CRM+ defect
Authors: Guella Ilaria , Soldà Giulia , Spena Silvia , Asselta Rosanna , Ghiotto Rossella , Tenchini Maria , Castaman Giancarlo , Duga Stefano
Published: February 2008

Severe factor XI (FXI) deficiency is a bleeding disorder generally inherited as an autosomal recessive trait and characterized by haemorrhagic symptoms mainly associated with injury or surgery. So far, more than 150 causative molecular defects have been identified throughout the F11 gene. In the present study, we investigated the molecular basis of FXI deficiency in two Italian patients. Mutational screening of the F|| gene disclosed a novel missense substitution (Arg184Gly) in exon 7 and two splicing mutations: a novel G>A transition affecting the last nucleotide of exon 4 (325G>A), and the already known IVS6+3A>G. RT-PCR assays were performed on total RNA extracted from platelets and lymphocytes of each patient. Se- quencing of RT-PCR products demonstrated that both 325G>A and IVS6+3A>G mutations abolish the corresponding donor splice site, causing the skipping of the affected exon; this in turn results in a frameshift introducing a premature termination codon. Expression of recombinant FXI-Arg184Gly revealed a 70% reduction in FXI activity, suggesting that the Arg184Gly mutation might cause a cross-reactive material positive (CRM+) deficiency. In conclusion, the functional consequences of two splicing mutations leading to FXI deficiency have been elucidated. Moreover, we report a novel missense mutation in the FIX-binding region of the FXI A3 domain leading to a CRM+ deficiency.
Atmospheric Horizontal Resolution Affects Tropical Climate Variability in Coupled Models
Authors: Navarra A. , Gualdi S. , Masina S. , Behera S. , Luo J.-J. , Masson S. , Guilyardi E. , Delecluse P. , Yamagata T.
Published: February 2008

The effect of atmospheric horizontal resolution on tropical variability is investigated within the modified Scale Interaction Experiment (SINTEX) coupled model, SINTEX-Frontier (SINTEX-F), developed jointly at Istituto Nazionale di Geofisica e Vulcanologia (INGV), L’Institut Pierre-Simon Laplace (IPSL), and the Frontier Research System. The ocean resolution is not changed as the atmospheric model resolution is modified from spectral resolution 30 (T30) to spectral resolution 106 (T106). The horizontal resolutions of the atmospheric model T30 and T106 are investigated in terms of the coupling characteristics, frequency, and variability of the tropical ocean–atmosphere interactions. It appears that the T106 resolution is generally beneficial even if it does not eliminate all the major systematic errors of the coupled model. There is an excessive shift west of the cold tongue and ENSO variability, and high resolution also has a somewhat negative impact on the variability in the east Indian Ocean. A dominant 2-yr peak for the Niño-3 variability in the T30 model is moderated in the T106 as it shifts to a longer time scale. At high resolution, new processes come into play, such as the coupling of tropical instability waves, the resolution of coastal flows at the Pacific–Mexican coasts, and improved coastal forcing along the coast of South America. The delayed oscillator seems to be the main mechanism that generates the interannual variability in both models, but the models realize it in different ways. In the T30 model it is confined close to the equator, involving relatively fast equatorial and near-equatorial modes, and in the high-resolution model, it involves a wider latitudinal region and slower waves. It is speculated that the extent of the region that is involved in the interannual variability may be linked to the time scale of the variability itself.
The Diurnal Cycle of Precipitation over the North American Monsoon Region during the NAME 2004 Field Campaign
Authors: Becker Emily J. , Berbery Ernesto Hugo
Published: February 2008

The structure of the diurnal cycle of warm-season precipitation and its associated fields during the North American monsoon are examined for the core monsoon region and for the southwestern United States, using a diverse set of observations, analyses, and forecasts from the North American Monsoon Experiment field campaign of 2004. Included are rain gauge and satellite estimates of precipitation, Eta Model forecasts, and the North American Regional Reanalysis (NARR). Daily rain rates are of about the same magnitude in all datasets with the exception of the Climate Prediction Center (CPC) Morphing (CMORPH) technique, which exhibits markedly higher precipitation values.

The diurnal cycle of precipitation within the core region occurs earlier in the day at higher topographic elevations, evolving with a westward shift of the maximum. This shift appears in the observations, reanalysis, and, while less pronounced, in the model forecasts. Examination of some of the fields associated with this cycle, including convective available potential energy (CAPE), convective inhibition (CIN), and moisture flux convergence (MFC), reveals that the westward shift appears in all of them, but more prominently in the latter.

In general, warm-season precipitation in southern Arizona and parts of New Mexico shows a strong effect due to northward moisture surges from the Gulf of California. A reported positive bias in the NARR northward winds over the Gulf of California limits their use with confidence for studies of the moist surges along the Gulf; thus, the analysis is complemented with operational analysis and the Eta Model short-term simulations. The nonsurge diurnal cycle of precipitation lags the CAPE maximum by 6 h and is simultaneous with a minimum of CIN, while the moisture flux remains divergent throughout the day. During surges, CAPE and CIN have modifications only to the amplitude of their cycles, but the moisture flux becomes strongly convergent about 6 h before the precipitation maximum, suggesting a stronger role in the development of precipitation.
Tropical Cyclone–Induced Upper-Ocean Mixing and Climate: Application to Equable Climates
Authors: Korty Robert L. , Emanuel Kerry A. , Scott Jeffery R.
Published: February 2008

Tropical cyclones instigate an isolated blast of vigorous mixing in the upper tropical oceans, stirring warm surface water with cooler water in the thermocline. Previous work suggests that the frequency, intensity, and lifetime of these storms may be functions of the climate state, implying that transient tropical mixing could have been stronger during warmer equable climates with higher concentrations of carbon dioxide. Stronger mixing of the tropical oceans can force the oceans’ meridional heat flux to increase, cooling tropical latitudes while warming higher ones. This response differs significantly from previous modeling studies of equable climates that used static mixing; coupling mixing to climate changes the dynamic response. A parameterization of mixing from tropical cyclones is developed, and including it leads to a cooling of tropical oceans and a warming of subtropical waters compared with control cases with fixed mixing. The mixing penetration depth regulates the magnitude of the response.