bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine Inhibits Tissue Factor Expression by LPS-stimulated Human Monocytes: Involvement of the A3 Adenosine Receptor
Authors: Broussas Matthieu , Cornillet-Lefèbvre Pascale , Potron Gérard , Nguyên Philippe 
Published: March 2018

SummaryTissue Factor (TF), an integral membrane glycoprotein that initiates the extrinsic pathway of blood coagulation, is thought to play a major part in coronary acute events. Adenosine, an endogenous nucleoside produced by the degradation of intracellular adenosine triphosphate, has been shown to exert many cardioprotective effects via an inhibition of platelets and neutrophils. This study was conducted to determine whether adenosine (ADO) could modulate the expression of TF by human monocytes. We found that ADO inhibited TF antigen and activity on endotoxin-stimulated monocytes in a dose-dependent manner. The mechanism was at least pre-translational since ADO caused a change in the TF mRNA level. Using ADO receptor-specific analogs, we showed that highly selective A3 agonist N6-(3-iodobenzyl)-adenosine-5’-N’-methyluronamide (IB-MECA) inhibited LPSinduced TF activity expression more potently than A1 agonist R-phenylisopropyladenosine (R-PIA) and A2 agonist CGS 2180. Furthermore, A1/A3 antagonist, xanthine amine congener (XAC) blocked the effect of ADO whereas A2a, A2b and A1 antagonists were ineffective. In addition, we observed that ADO agonists inhibited monocyte TF expression in LPS-stimulated whole blood. The rank order of agonist potency suggested that A2 and A3 receptors might be involved (2-Cado > CGS = IB-MECA > R-PIA). This was supported by the fact that A2 and A3 antagonists reversed the action of 2-Cado. We conclude that TF inhibition by ADO on human purified monocytes involved A3 receptors.
Ramipril Prior to Thrombolysis Attenuates the Early Increase of PAI-1 in Patients with Acute Myocardial Infarction
Authors: Wagner Andreas , Herkner Harald , Schreiber Wolfgang , Bur Andreas , Woisetschläger Christian , Stix Günther , Laggner Anton , Hirschl Michael 
Published: March 2018

SummaryIn a placebo-controlled, double-blinded, randomized study we evaluated the effect of ramipril prior to thrombolysis on the course of PAI-1 plasma levels and on the frequency of postinfarct ischemic events in patients with acute myocardial infarction. Fifty-one out of 99 patients received 2.5 mg ramipril orally prior to thrombolysis and 12 h later. The blood samples for determination of PAI-1 plasma levels were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis. Postinfarct ischemic events were registered until coronary angiography was performed and defined as recurrent chest pain and/or evidence of ischemic signs on the ECG (ST-depression or ST-segment elevation of 1 mm in one or more inferior or anterior leads). Coronary angiography was performed within 7 days after the onset of myocardial infarction. Patients were classified into two groups: those without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and those with reperfusion of the infarct-related artery (TIMI grade 2,3). On admission, PAI-1 plasma levels were similiar in both groups (ramipril: 47.1 [4.8] ng/ml; placebo: 49.1 [4.8] ng/ml). The PAI-1AUC was 77.2 [6.7] ng/ml/h in the ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013). Significant differences between groups were observed at 4, 8 and 12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p < 0.01; 8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p < 0.01; 12 hrs: 71.3 (9.5) vs. 87.4 (7.7) ng/ml, p < 0.05). The relative frequency of postinfarct ischemic events was significantly lower in the ramipril group (2.5% versus 7.1%, p = 0.001). Additionally, we observed a significant higher rate of TIMI grade 2 and 3 of the infarct-related artery in patients receiving oral ramipril compared to the placebo group (73% versus 54%; p = 0.035).Our study demonstrates a favorable effect of ramipril on the fibrinolytic system after thrombolysis associated with a lower rate of postinfarct ischemic events within the first days after myocardial infarction. Therefore, the application of ramipril prior to thrombolysis appears to be a reasonable concomitant treatment which may reduce early infarctrelated complications.
Chemotherapy-Induced Activation of Hemostasis: Effect of a Low Molecular Weight Heparin (Dalteparin Sodium) on Plasma Markers of Hemostatic Activation
Authors: Weitz Ilene , Israel Valerie , Waisman James , Presant Cary , Rochanda Leanne , Liebman Howard 
Published: March 2018

SummaryTo evaluate the effect of standard chemotherapeutic regimens on the hemostatic profile of patients with breast and lung carcinoma; and to evaluate the effect of a single dose of a low molecular weight (LMW) heparin, dalteparin sodium, administered prior to the chemotherapy on markers of hemostatic activation.11 patients with breast cancer and 10 patients with lung cancer receiving systemic chemotherapy were studied. 10 breast cancer patients and 9 lung cancer patients completed at least 1 cycle of treatment and had all hemostatic studies. Patients had a complete hemostatic and prothrombotic profile performed at study initiation. Markers of hemostatic activation consisting of immunoassays for thrombin-antithrombin (TAT) complex and D-dimer were measured in plasma samples obtained prior to chemotherapy and at 1, 24 and 48 h after treatment. A 2500 U dose of dalteparin was given prior to the 2nd cycle of chemotherapy; 5000 U of dalteparin was given prior to the 4th treatment cycle.Chemotherapy resulted in statistically significant increases in TAT and D-dimer for the 1, 24 and 48 h plasma samples in both the breast and lung cancer patients for all cycles of chemotherapy given without LMW heparin. There were statistically significant increases in basal thrombin generation over the 4 cycles of treatment which was unrelated to active cancer. Both pretreatment doses of dalteparin effectively prevented increases in the markers of hemostatic activation. However, in the lung cancer patients, who had significantly increased basal thrombin generation, the 5000 U dose dalteparin was more effective.Chemotherapy results in significant hemostatic activation in patients with breast and lung cancer. The effect of treatment appears to be cumulative. A single dose of LMW heparin administered prior to therapy can suppress hemostatic activation.This project was funded by a grant from the Pharmacia corporation
Inhibition of Thrombin Generation in Plasma by Fibrin Formation (Antithrombin I)
Authors: de Bosch N. B. , Ruiz-Sáez A. , Echenagucia M. , Rodriguez-Lemoin A. , Mosesson M. W. 
Published: March 2018

SummaryThe adsorption of thrombin to fibrin during clotting defines “Antithrombin I” activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (‘γA/’γA), whose fibrin has two “low affinity” non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (‘γ´/’γA), which in addition to low affinity thrombin-binding sites in fibrin, has a “high affinity” non-substrate thrombin binding site in the carboxy-terminal region of its ‘γ´ chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or ‘γ´ 414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.Presented in part at the XVII Congress of the ISTH, Washington, D. C. (1)
Intracellular Factor XIII Crosslinks Platelet Cytoskeletal Elements upon Platelet Activation
Authors: Serrano Katherine , Devine Dana 
Published: March 2018

SummaryThe platelet cytoplasm contains approximately half of the factor XIII (FXIII) transglutaminase content circulating in blood, yet the function of cytoplasmic FXIII is poorly understood. This study investigated functions of platelet FXIII in internal platelet processes by studying the interactions of FXIII with platelet cytoskeletal proteins. FXIII was present in cytoskeletal fractions of platelet lysate separated by centrifugation. When cytoskeletal fractions were immobilized on nitrocellulose membranes, thrombin-activated rFXIII (rFXIIIa*) or calcium iontreated rFXIII (rFXIIIa°) bound to some of these proteins, whereas untreated rFXIII did not. Utilizing fluorescence microscopy, an actin polymerization-dependent transient translocation of FXIII from a diffuse homogeneous distribution throughout the cytoplasm to the platelet periphery was observed upon platelet activation, suggesting an association with cytoskeletal proteins. Transglutaminase activity increased in cytoskeletal fractions of activated versus non-activated platelets. Immunoblotting analysis of platelet cytoskeletal fractions identified filamin and vinculin as being crosslinked upon platelet activation.
Quenching of Intracellular ROS Generation as a Mechanism for Oleate-Induced Reduction of Endothelial Activation and Early Atherogenesis
Authors: Massaro Marika , Basta Giuseppina , Lazzerini Guido , Carluccio Maria , Bosetti Francesca , Solaini Giancarlo , Visioli Francesco , Paolicchi Aldo , De Caterina Raffaele 
Published: March 2018

SummaryWe previously showed that the exposure of vascular endothelium to oleate results in reduced endothelial activation. We now investigate possible mechanisms for this effect in relation to generation of reactive oxygen species (ROS). We stimulated several types of endothelial cells with cytokines or lipopolysaccharide, with or without preincubation with 10-100 µmol/L oleate. Oleate preincubation reduced VCAM-1 expression in all cell types, as well as macrophage-colony stimulating factor release. We simultaneously measured the concentration of intracellular glutathione (GSH), the activity of GSH-related antioxidant enzymes and the production of intracellular ROS. Stimulation of endothelial cells caused a decrease of GSH and an increase in intracellular ROS. The addition of oleate before stimulation, prevented the depletion of GSH and partially prevented stimuli-induced increase of intracellular ROS. This occurred without any change in the activity of GSH-related antioxidant enzymes, superoxide dismutase and catalase. Furthermore, in a cell-free superoxide anion-generating system, oleate quenched the generation of ROS. These results indicate that oleate may exert direct vascular atheroprotective effects by inhibiting endothelial activation through a quenching of stimuli-induced increase in ROS.
Standardisation of von Willebrand Factor in Therapeutic Concentrates: Calibration of the 1st International Standard for von Willebrand Factor Concentrate (00/514)
Authors: Sands Dawn , Chang Andrew , Mazurier Claudine , Hubbard Anthony 
Published: March 2018

SummaryAn international study involving 26 laboratories assayed two candidate von Willebrand Factor (VWF) concentrates (B and C) for VWF:Antigen (VWF:Ag), VWF:Ristocetin Cofactor (VWF:RCo) and VWF:Collagen binding (VWF:CB) relative to the 4th International Standard Factor VIII/VWF Plasma (4th IS Plasma) (97/586). Estimates of VWF:Ag showed good agreement between different methods, for both candidates, and the overall combined means were 11.01 IU/ml with inter-laboratory variability (GCV) of 10.9% for candidate B and 14.01 IU/ml (GCV 11.8%) for candidate C. Estimates of VWF:RCo showed no significant difference between methods for both candidates and gave overall means of 9.38 IU/ml (GCV 23.7%) for candidate B and 10.19 IU/ml (GCV 24.4%) for candidate C. Prior to the calibration of the candidates for VWF:CB it was necessary to calibrate the 4th IS Plasma relative to local frozen normal plasma pools; there was good agreement between different collagen reagents and an overall mean of 0.83 IU per ampoule (GCV 11.8%) was assigned. In contrast, estimates of VWF:CB in both candidates showed large differences between collagen reagents with inter-laboratory GCV’s of 40%. Candidate B (00/514) was established as the 1st International Standard von Willebrand Factor Concentrate by the WHO Expert Committee on Biological Standardisation in November 2001 with assigned values for VWF:Ag (11.0 IU/ampoule) and VWF:RCo (9.4 IU/ampoule). Large inter-laboratory variability of estimates precluded the assignment of a value for VWF:CB.
Inhibition of ADP-induced P-selectin Expression and Platelet-Leukocyte Conjugate Formation by Clopidogrel and the P2Y12 Receptor Antagonist AR-C69931MX but not Aspirin
Authors: Judge Heather , Wilcox Robert , Heptinstall Stan , Storey Robert 
Published: March 2018

SummaryPlatelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.
Intravascular tissue factor pathway – a model for rapid initiation of coagulation within the blood vessel
Authors: Luther Thomas , Müller Ingrid , Engelmann Bernd 
Published: March 2018

SummaryThe loss of blood through vessel wall ruptures is initially prevented by the rapid adhesion of platelets to the subendothelium, and the formation of a thrombus consisting of platelets and different types of leukocytes. Concomitantly, the coagulation process is thought to be activated by vascular wall tissue factor (TF). Here, a new model for the initiation of coagulation is presented, based on unexpected findings on the presence and functional activation of TF within the blood itself. TF was recently found to be stored in the α-granules of resting platelets under physiological conditions. Activation by collagen exposes TF on the platelet cell membrane and on platelet derived microvesicles. Adhesive interactions of the TF bearing platelets and microvesicles to neutrophils and monocytes support the functional activation of the blood based TF. The intravascular TF pathway is proposed to play a significant role during hemostasis by enabling the generation of fibrin at the site of the developing thrombus.
Interaction of pathogens with the endothelium
Authors: Suttorp Norbert , Hippenstiel Stefan 
Published: March 2018

SummaryThe endothelium lines the inner surface of the vessel wall establishing a multifunctional, semi-permeable cellular barrier at blood-tissue interface. The large total surface of the endothelium is exposed to pathogens, pathogen-derived products as well as to agents of the activated host defense during an inflammatory reaction. The endothelium is not only specifically targeted by important infective agents like Rickettsiae (1) or Bartonella (2), it is involved in virtually most, if not all, acute inflammatory responses. Pathogens attack the endothelium by a wide variety of strategies, as different as activation of preformed receptor-mediated pathways in the endothelium, release of pore-forming exotoxins or intracellular replication and chronic parasitism. These pathophysiological forces affect the endothelial phenotype, resulting in endothelial barrier dysfunction, increased leukocyte-endothelial interaction, mediator release, and procoagulant activity. Moreover, endothelial responses retroact on the invading pathogen as well as on the host defense resulting in a complex and dynamic interaction (Fig. 1). Endothelial activation contributes considerably to inflammation and resulting clinical characteristics. In this context the endothelium is not just a passive victim, it rather aggravates the ongoing struggle with the pathogen. In this review we focus on some important mechanisms of the cellular microbiology of endothelial infection by bacteria and viruses.
Antithrombotic activity of LB30057, a newly synthesized direct thrombin inhibitor
Authors: Kang Kyu-Tae , Jung Byoung-In , Bae Ok-Nam , Lee Moo-Yeol , Chung Seung-Min , Lee Joo-Young , Lee Sang-Koo , Kim In-Chul , Chung Jin-Ho 
Published: March 2018

SummaryAn amidrazonophenylalanine derivative, LB30057, inhibits the catalytic activity of thrombin potently by interaction with the active site of thrombin, and has high water solubility. In the present study, we evaluated the effect of LB30057 on the biological activities of thrombin at various tissues, and determined whether thrombin inhibition by LB30057 could reduce the incidence of occlusive thrombosis in an in vivo animal model. Treatment with LB30057 to human plasma prolonged clotting times in a concentration-dependent manner. LB30057 suppressed significantly thrombin-induced phosphatidylserine (PS) exposure in platelets, suggesting that LB30057 could inhibit blood coagulation accelerated by PS exposure. In human platelets, soluble thrombin- and clot-induced platelet aggregation was inhibited by LB30057 potently. Consistent with this finding, LB30057 showed concentration-dependent inhibitory effects on serotonin secretion and P-selectin expression induced by thrombin in platelets. In the blood vessel isolated from the guinea pig, treatment with LB30057 resulted in a concentration-dependent inhibition of thrombin-induced vascular contraction. In vivo study revealed that LB30057 following oral administration significantly increased the time to occlusion and improved carotid arterial patency using rat carotid artery thrombosis model. All these results suggest that LB30057 is a potent inhibitor of biological activities of thrombin at various target tissues and, therefore, might be developed as an anti-thrombotic agent for treatment and prevention of thrombotic diseases.
Platelet phosphatidylserine exposure and procoagulant activity in clotting whole blood – different effects of collagen, TRAP and calcium ionophore A23187
Authors: Rånby Mats , Lindahl Tomas , Ramström Sofia 
Published: March 2018

SummaryWe have studied the effects of different platelet agonists on phosphatidylserine (PS) exposure and clotting times in blood without anticoagulants. Similar reductions in clotting time were obtained for collagen, TRAP-6 or calcium ionophore A23187 (50 μmol/L), in spite of huge differences in PS expression [6.7 ± 2.4%, 2.3 ± 0.5% and 99.9 ± 0.1%, respectively (mean ± SD, n = 5)]. Furthermore, the clotting times were much longer for samples with A23187 exposing the same amounts of PS as samples with collagen or TRAP-6. Annexin V reversed the clotting time reduction, but could not prevent coagulation. Addition of phospholipid vesicles containing 20% PS neither affected the clotting times nor induced clotting in recalcified, platelet-free plasma.We conclude that platelet PS exposure is necessary, but not sufficient, for the coagulation amplification observed when platelets are stimulated via physiological receptors in a whole blood environment.
Prevention of Venous Thromboembolism in Internal Medicine with Unfractionated or Low-molecular-weight Heparins: A Meta-analysis of Randomised Clinical Trials
Authors: Laporte-Simitsidis Silvy , Tardy Bernard , Cucherat Michel , Buchmüller Andréa , Juillard-Delsart Daphné , Decousus Hervé , Mismetti Patrick 
Published: March 2018

SummaryThe prevention of venous thromboembolic disease is less studied in medical patients than in surgery.We performed a meta-analysis of randomised trials studying prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in internal medicine, excluding acute myocardial infarction or ischaemic stroke. Deepvein thrombosis (DVT) systematically detected at the end of the treatment period, clinical pulmonary embolism (PE), death and major bleeding were recorded.Seven trials comparing a prophylactic heparin treatment to a control (15,095 patients) were selected. A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions = 56% and 58% respectively, p <0.001 in both cases), without significant difference in the incidence of major bleedings or deaths. Nine trials comparing LMWH to UFH (4,669 patients) were also included. No significant effect was observed on either DVT, clinical PE or mortality. However LMWH reduced by 52% the risk of major haemorrhage (p = 0.049).This meta-analysis, based on the pooling of data available for several heparins, shows that heparins are beneficial in the prevention of venous thromboembolism in internal medicine.
The Half-life of Infused Factor VIII Is Shorter in Hemophiliac Patients with Blood Group 0 than in those with Blood Group A
Authors: Mauser-Bunschoten Evelien , Zarkova Antoanette , Haan Els , Kruitwagen Cas , Sixma Jan , van den Berg H. , Vlot André 
Published: March 2018

SummaryA considerable inter-individual variation in half-life of infused factor VIII is observed among patients with hemophilia A. The factors contributing to this wide range in factor VIII half-life are not known in detail. We analysed the pharmacokinetics of infused factor VIII in 32 patients with hemophilia A, comprising 20 brothers from 10 families, 3 and 4 brothers from 2 families, and 5 patients from 5 single families, respectively. Multiple linear regression analysis was used to asses the effect of several variables on factor VIII half-life. We found that the pre-infusion von Willebrand factor antigen levels (vWF:Ag) were positively correlated with factor VIII half-life (r = 0.52, p = 0.002), i. e., each variable was associated with about 27% of the variance of the other. In fraternal pairs, familial clustering was significant for AB0 blood group (p < 0.001), but could not be detected for factor VIII half-lives or pre-infusion vWF:Ag levels. vWF:Ag level (p = 0.001) and AB0 blood group (p = 0.003) significantly determined factor VIII half-life, whereas age, length, bodyweight, the presence or absence of a factor VIII gene inversion, and Rhesus phenotype did not. Patients with blood group 0 exhibited a statistically significant shorter factor VIII half-life than patients with blood group A (15.3 versus 19.7 h, respectively) (p = 0.003). Patients with blood group A and 0 differ in respect to the presence of anti-A antibodies in the latter. It is possible that these anti-A antibodies interact with endogenous vWF, thus affecting the half-life time of the factor VIII/vWF complex.