bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating ICAM-1 and VCAM-1 in Peripheral Artery Disease and Hypercholesterolaemia: Relationship to the Location of Atherosclerotic Disease, Smoking, and in the Prediction of Adverse Events
Authors: Seigneur Martine , Steiner Michael , Miller J. , McCollum Charles , Blann Andrew 
Published: March 2018

SummaryWe examined the relationship of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) with smoking and hypercholesterolaemia in peripheral artery disease (PAD). Serum samples were obtained from 119 patients with objectively-proven PAD, 39 patients with hypercholesterolaemia but asymptomatic for PAD, and 132 age and sex matched asymptomatic controls. Using ELISAs, we found increased sICAM-1 and sVCAM-1 (both p <0.01) in the patients with PAD relative to the controls, but no significant change in patients with hypercholesterolaemia. However, the effect for sVCAM-1 was lost when smoking was entered as a covariate. Only sICAM-1 was higher in patients with PAD in the femoral/iliac arteries compared to the carotid arteries (p <0.05). In a 39-month follow-up of 112 patients with PAD, increased ICAM-1 weakly (univariate p <0.05) predicted those 57 whose disease progressed (i.e. to end points such as myocardial infarction and arterial surgery). However, high fibrinogen was a much better (univariate p = 0.001, multivariate p <0.05) predictor of disease progression. We suggest (i) that increased levels of sVCAM-1 in atherosclerosis are due to smoking, (ii) that increased sICAM-1 is independent of this risk factor, (iii) that both these changes are independent of hypercholesterolaemia, and (iv) that increased sICAM-1 is a weak predictor of disease progression in peripheral atherosclerosis.
Evaluation of Thrombopoiesis in Thrombocytopenic Disorders by Simultaneous Measurement of Reticulated Platelets of Whole Blood and Serum Thrombopoietin Concentrations
Authors: Yoneyama Akiko , Shirai Jun , Ishida Tateru , Shoda Eriko , Miyazaki Kouji , Sunaga Sinji , Horie Ryoichi , Aoki Katunori , Koike Kazuhiko , Ogata Iturou , Tahara Tomoyuki , Kato Takashi , Nakahara Kazuhiko , Kariya Toshitugu , Higashihara Masaaki , Koike Yukako 
Published: March 2018

SummaryTo evaluate thrombopoiesis in thrombocytopenic disorders, we simultaneously determined reticulated platelet counts in whole blood by FACScan flow cytometry and serum thrombopoietin (TPO) concentrations by a sensitive sandwich ELISA. The subjects were 40 healthy volunteers and 45 thrombocytopenic patients. In idiopathic thrombocytopenic purpura (ITP), the percentage of reticulated platelets was significantly elevated (5.61 ± 2.02%: mean ± SD) relative to normal controls (2.17 ± 0.90%), but serum TPO concentrations (1.91 ± 1.27 fmol/l) did not differ significantly from the normal range (1.43 ± 0.62 fmol/l). The patients with aplastic anemia (AA) had decreased reticulated platelet counts and markedly increased serum TPO concentrations (13.65 ± 10.64 fmol/l). In thrombocytopenic patients with liver cirrhosis (LC), the absolute number of reticulated platelets (1.65 ± 1.11 × 109/l) decreased similarly that in AA. However, serum TPO concentrations (1.38 ± 0.50 fmol/l) did not increase in contrast to AA. Our findings suggested a possible dual mechanism of thrombocytopenia in LC; that is, thrombocytopenia in LC results from the decreased TPO production primarily in the liver adding to an increase in platelet sequestration in the spleen.
Increased Potency and Decreased Elimination of Lamifiban, a GPIIb-IIIa Antagonist, in Patients with Severe Renal Dysfunction
Authors: Nordal Knut , Midtvedt Karsten , Goggin Timothy , Brosstad Frank , Lehne Gustav 
Published: March 2018

SummaryActivation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (IV). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the anti-platelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.
Regulation of Gelatinase Activity in Mice with Targeted Inactivation of Components of the Plasminogen/Plasmin System
Authors: Silence J. , Lemmens G. , Frederix L. , Collen D. , Lijnen H. R. 
Published: March 2018

SummaryTo investigate a potential physiological role of the plasminogen/ plasmin system in activation of the matrix metalloproteinase (MMP) system, the distribution of latent and active MMP-2 (gelatinase A) or MMP-9 (gelatinase B) was monitored in aorta extracts and in serum-free conditioned cell culture medium obtained from wild-type (WT) mice and from mice with deficiency of tissue-type plasminogen activator (t-PA–/–), urokinase-type plasminogen activator (u-PA–/–), plasminogen activator inhibitor-1 (PAI-1–/–) or plasminogen (Plg–/–).In aorta extracts, the contribution of active MMP-2 to the total MMP-2 level ranged between 7 and 16% for the different genotypes, whereas active MMP-9 was not detected.The contribution of active 58 kDa MMP-2 to the total MMP-2 level (active plus latent) ranged between 14 and 29% (mean of 3 experiments) for fibroblasts of the different genotypes, and between 18 and 32% for smooth muscle cells, and was relatively constant in time (7-72 h). The contribution of active 83 kDa MMP-9 to the total MMP-9 level ranged between 15 and 29% for fibroblasts of the different genotypes and was relatively constant in time (24-72 h); corresponding values were 17 to 57% for smooth muscle cells, with the exception of Plg–/– smooth muscle cells which had undetectable levels of active MMP-9. Addition of plasmin(ogen) to the cell culture medium of fibroblasts did not significantly affect the distribution of active and latent MMP-2, but resulted in an approximately two-fold enhancement of the contribution of active MMP-9. In macrophages of Plg–/– mice, active MMP-9 was detected only when the cells were cultured in the presence of plasminogen.These data indicate that activation of proMMP-2 occurs independently of the physiological plasminogen activators and of plasmin(ogen) in all the cell types evaluated. Activation of proMMP-9 was enhanced in the presence of plasmin(ogen), but active MMP-9 was also detected in fibroblasts of Plg–/– mice, indicating that in vivo activation may occur via plasmin(ogen)-independent mechanisms.
Neutrophils Rolling on Immobilised Platelets Migrate into Homotypic Aggregates after Activation
Authors: Buckley Christopher , Simmons David , Nash Gerard , Rainger G. E. 
Published: March 2018

SummaryInteractions between platelets and leucocytes are implicated in the pathology of thrombotic vascular disease. Using a flow-based adhesion assay we have investigated a novel route for the formation of neutrophil aggregates on the surface of immobilised activated platelets. Neutrophils perfused over a platelet monolayer formed numerous rolling attachments but rapidly stopped and spread after the superfusion of N-formyl-methionyl-leucyl-phenylalanine or platelet-activating factor (both at 10–7 M). Subsequent integrin-mediated migration across the platelet monolayer enabled formation of homotypic neutrophil aggregates, which was significant within 2.5 min of receipt of either stimulus. Aggregates increased in size with time and had an average projected area of ~500 μm2 after 10 min. Increasing size was correlated with an increasing tendency for movement downstream and large aggregates sometimes tumbled in that direction. The formation and stability of homotypic aggregates was dependent on several adhesive mechanisms. Antibody blockade demonstrated that interactions involving CD11a/ CD18 and ICAM-3, between αvβ3-integrin and CD31 and between L-selectin and an unidentified counter-ligand were all required for the complete aggregatory response. Furthermore, blockade of L-selectin allowed initial aggregation which then reversed, suggesting that this receptor might regulate the interactions between other adhesion molecules that directly supported cell-cell adhesion. We propose that this novel route for leucocyte aggregation could promote vascular occlusion in thrombotic vessels or at distal sites in the event of embolisation.
A Three-Dimensional Consideration of Variant Human Fibrinogens
Authors: Everse Stephen , Spraggon Glen , Doolittle Russell 
Published: March 2018

SummaryRecently reported X-ray structures for large core fragments derived from human fibrinogen and fibrin make it possible to correlate structural and functional anomalies of known genetic variants. Here we examine a variety of amino acid replacements previously reported for hereditary dysfibrinogenemias, most of which are associated with impaired fibrin polymerization. For many of these we have modeled in the mutant amino acid and considered the structural consequences. We have also examined the cases of a small deletion and a large insertion, as well as the impact of substitutions in the GPRPam ligand that was co-crystallized with fragment double-D.
Heparin and Cancer
Authors: Ornstein Deborah , Zacharski Leo 
Published: March 2018

SummaryHeparin has been the subject of intensive investigation for decades by both basic and clinical scientists because of its usefulness as a therapeutic anticoagulant (1). In addition to its effects on coagulation, however, heparin exhibits many other activities which seem to have little to do with anticoagulation (2). Goerner first observed an effect on the natural history of malignancy in 1930 when he demonstrated that heparin inhibited tumor growth in experimental animals (3). A substantial body of literature on heparin and cancer has developed during the ensuing decades. A recent increase in interest has resulted from observations made during prospective, randomized clinical trials which compared unfractionated heparin (UH) with low molecular weight heparin (LMWH) for the prevention and treatment of venous thromboembolism (VTE). Several studies have shown improvement in short to intermediate term survival in the subset of patients with cancer who received LMWH. This improved outcome has been emphasized in two published meta-analyses (4, 5), and the trend is supported by the results of a more recent prospective study (6). The improved cancer outcome could not be attributed to prevention of VTE in any of the studies; therefore, it is reasonable to hypothesize that a beneficial effect of heparin may be mediated by mechanisms independent of anticoagulation.Heparin has several properties that may plausibly explain its effect on experimental and human malignancy. The purpose of this paper is to summarize the literature on heparin and cancer and review mechanisms by which heparin may exert antineoplastic activity. The goal is to encourage both definitive clinical trials of heparin on cancer outcome and further studies of drug mechanisms in human malignancy. LMWH, with its favorable pharmacokinetic attributes, is suitable for chronic outpatient administration and is an excellent candidate for further investigation. Such a departure from conventional experimental cytotoxic chemotherapy holds promise for development of novel forms of growth regulatory therapy that interrupt pathways of cancer progression. In this review, “heparin” will refer to unfractionated heparin (UH), and “UH” and “LMWH” will be used to distinguish between the two molecular forms.
Comparison between von Willebrand Factor (VWF) and VWF Antigen II in Normal Individuals and Patients with von Willebrand Disease
Authors: Mazurier Claudine , Romeuf Christophe de 
Published: March 2018

SummaryVon Willebrand disease is characterised by a quantitative (type 1) or qualitative (type 2) decrease in von Willebrand factor (vWF) a multimeric glycoprotein involved in primary haemostasis. The propep-tide of von Willebrand, also named vWF antigen II (vWF:AgII), is released from platelets and endothelial cells and circulates in plasma as a glycoprotein of 100 kD. In the present study, we attempted to determine whether vWF:AgII level may provide information on the synthesis of vWF, specially in patients with von Willebrand disease (vWD). To elucidate that point, we developed an ELISA and quantify the vWF:AgII in normal individuals and in various vWD patients. The propeptide molar concentration was found to be 5nM as compared to 31 nM for mature vWF. In normal individuals, the level of vWF:AgII was significantly decreased in females from O and A blood groups. In type 2 vWD patients the level of plasma vWF:AgII appears normal in the patients with normal level of platelet vWF. In type 2 B vWD characterised by increased affinity of mature vWF for platelet glyco-protein Ib, the vWF:Ag II in contrast to the vWF antigen (vWF:Ag) was not decreased. In type 2A vWD patients the level of vWF:AgII was decreased in patients with absence of high molecular weight vWF in platelets and plasma but normal in patients with increased sensitivity to proteolysis. Finally, in type 1 vWD, some studied patients have a parallel decrease in vWF:AgII and vWF:Ag whereas in others, the vWF:Ag levels were much more affected than corresponding vWF:AgII levels, as observed in some type 2 vWD patients. Thus, in contrast to that already described, the plasma vWF:AgII level cannot discriminate type 1 from type 2 vWD patients. We conclude that the vWF:AgII measurement provides additional information on the mechanisms responsible for vWD and might also contribute to the classification of vWD patients.
Monitoring Heparin Therapy Using Activated Partial Thromboplastin Time – Results of a Multicenter Trial Establishing the Therapeutic Range for SILIMAT, a Reagent with High Sensitivity to Heparin
Authors: Boutière Brigitte , Horellou Marie-Hélène , Trzeciak Marie Christine , Samama Meyer , Toulon Pierre 
Published: March 2018

SummaryAPTT is widely used for laboratory monitoring of treatment with unfractionated heparin (UFH). However, since its sensitivity to heparin varies significantly from one reagent to another, the therapeutic range had to be defined for each brand of APTT reagent. As an example, SILIMAT (bio-Mérieux) is a new APTT reagent containing rabbit brain phospholipids and micronized silica as an activator. Since its high sensitivity to heparin has been previously reported, a multicenter trial was carried out in an attempt to define the therapeutic range of APTT performed using this new reagent. For that purpose, 170 blood samples drawn for routine coagulation testing from 170 different patients treated with UFH were analyzed. A single batch of two different APTT reagents were used on KC10 coagulometers: SILIMAT and Automated APTT (Organon-Teknika) whereas the anti-Xa activity was evaluated by a chromogenic substrate-based assay. The same methodology was used in all the centers. In order to obtain a plasma anti-Xa activity within the therapeutic range i.e. between 0.30 and 0.70 IU/ml, the APTT ratios were found between 1.90 and 5.40 for SILIMAT, which corresponded to clotting times of the patients plasma between 63 and 178 s. The APTT ratios were significantly lower when evaluated using Automated APTT (between 1.70 and 4.10), with clotting times between 53 and 127 s. In addition, a good correlation was found between the Anti-Xa activity and APTT for both reagents (r >0.65). However, it is not possible to make recommendations regarding the therapeutic ranges without restrictions. Although about 70% of the patients with an anti-Xa activity between 0.30 and 0.70 IU/ml had an APTT in the above defined ranges, the degree of concordance between the two assays is not absolute. Actually more than 30% of the patients had discordant anti-Xa activity and APTT and more than a quarter of the patients included in the above defined therapeutic range for APTT had an anti-Xa activity outside the 0.30-0.70 IU/ml range, whatever the reagent used. In conclusion, to define the therapeutic ranges of APTT using the recommended method is practicable but some critical points could be raised, suggesting that a better method is awaited in order to improve the standardization.
Population Pharmacokinetics of Recombinant Factor VIIa in Volunteers Anticoagulated with Acenocoumarol
Authors: Nony Patrice , Erhardtsen Elisabeth , Delair Sylvie , Ffrench Patrick , Dechavanne Marc , Boissel Jean-Pierre , Girard Pascal 
Published: March 2018

SummaryThis study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 μg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous “endogenous perfusion” mimicking endogenous activity. Estimated clearance was 2.4 l/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses ≤20 μg/kg and 88 ml/kg for doses >20 μg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 μg/kg. The model will be used to better define the dosage regimen for future clinical developments.
Warfarin or Acenocoumarol: Which Is better in the Management of Oral Anticoagulants?
Authors: Barcellona Doris , Vannini Maria Luigia , Fenu Lara , Balestrieri Cinzia , Marongiu Francesco 
Published: March 2018

SummaryWarfarin is employed more frequently than acenocoumarol because of its longer half-life (36 h), theoretically providing more stable anticoagulation, and avoiding factor VII fluctuations that potentially occur during acenocoumarol treatment (half-life 10 h).The aim of our study was to compare acenocoumarol with warfarin in the same group of 103 patients who started oral anticoagulation with acenocoumarol and then changed to warfarin. In these patients we compared the previous period of six months on acenocoumarol treatment (July-December 1996) with a new six-month period on warfarin (July-December 1997). We wished to know whether warfarin could improve the quality and the stability of oral anticoagulation of our patients and whether there was a difference between the two drugs in the weekly mean dose per patient. Moreover in order to detect the possible daily fluctuation of factor VII, we evaluated a further group of 54 patients. A subgroup of these patients was treated with warfarin while another received acenocoumarol.In the first group of patients, 1,158 and 1,064 PTs were carried out with acenocoumarol and warfarin, respectively. The percentage of PTs in the therapeutic range was 59% with acenocoumarol and 62% with warfarin (p = 0.4). The mean number of visits per patient was 12 and 11, and the mean number of visits in the therapeutic range was 7 and 7, respectively. The last check in file method did not show any difference between the two drugs. Overdose states were 51 (4.4%) with acenocoumarol and 30 (2.8%) with warfarin (p = 0.4). A good correlation (r = 0.92) was found between the acenocoumarol and the warfarin weekly mean dose. The mean warfarin/acenocoumarol weekly dose ratio was 2.08 (range: 1.25-3.30; CI 95%: 1.99-2.16).In the second group of patients, factor VII levels with both drugs were higher 24 h after administration than 16 h after, showing that their daily fluctuation was independent of the drug’s half-life, since factor VII levels in patients with a low vitamin K intake were not increased.Our results showed that warfarin did not appear to be better than acenocoumarol in the performance of an Anticoagulation Clinic in terms of PTs within the therapeutic range per patient. It seems that the behaviour of factor VII was affected by the intake of vitamin K rather than by the short half-life of acenocoumarol.
Retrospective Neuropathological Review of Prion Disease in UK Haemophilic Patients
Authors: Ironside James , Bell Jeanne , Giangrande Paul , Ludlam Christopher , Esiri Margaret M. , McLaughlin James , Lee Christine 
Published: March 2018

SummaryIn 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.
Fibrate-modulated Expression of Fibrinogen, Plasminogen Activator Inhibitor-1 and Apolipoprotein A-I in Cultured Cynomolgus Monkey Hepatocytes
Authors: Kockx M. , Princen H. M. G. , Kooistra T. 
Published: March 2018

SummaryFibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes.We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα trans-activation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p <0.01) between PPARα transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARα transactivation activity (r = 0.47; p = 0.24), whereas such a correlation was absent for PAI-1 (r = 0.03; p = 0.95). These results strongly suggest an involvement of PPARα in the regulation of fibrinogen gene expression.