bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is a Prolonged Bleeding Time Associated with an Increased Risk of Hemorrhage after Liver Biopsy?
Authors: Brosstad Frank , Egeland Thore , Egge Tor , Schrumpf Erik , Boberg Kirsten 
Published: March 2018

SummaryBleeding time determination is not advised as a general preoperative hemostasis screening test, but it might be useful in some patient groups. Patients referred for liver biopsy frequently have coagulation disturbances and are at risk of hemorrhage. In this prospective study 219 liver biopsies were carried out regardless of a prolonged bleeding time, but with minimum requirements for hemoglobin concentration, platelet count, and tests of the internal and external coagulation pathways. The bleeding time was prolonged in the case of 48 (22%) of the biopsies. Significant bleeding as defined by a hemoglobin decrease of ≥2.0 g/dl occurred in nine patients. Three of these patients were bone marrow transplanted. Patients with a prolonged bleeding time carried a five times higher risk of bleeding (odds ratio = 5.0; confidence interval = 1.1-21.8; p = 0.019). We conclude that the bleeding time may give additional information on the risk of bleeding in some patient groups undergoing liver biopsy.
Activation of Plasminogen Activator Inhibitor-1 Synthesis by Phorbol Esters in Human Promyelocyte HL-60
Authors: Lopez Sophie , Peiretti Franck , Morange Pierre , Laouar Amale , Fossat Chantal , Bonardo Bernadette , Huberman Eliezer , Juhan-Vague Irène , Nalbone Gilles 
Published: March 2018

SummaryHL-60 cells treated by PMA develop the monocyte adherent pheno-type and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCβ gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCβ gene expression or transfected with PKCβ cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCβ.In conclusion, we propose that the pathway PKCβ-MEK-MAPK p42 is a potential linear route for PAI-1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells.
Platelet Activation Induced by Combined Effects of Anticardiolipin and Lupus Anticoagulant IgG Antibodies in Patients with Systemic Lupus Erythematosus
Authors: Suehisa Etsuji , Kuratsune Hirohiko , Machii Takashi , Koike Takao , Kitani Teruo , Kanakura Yuzuru , Amino Nobuyuki , Nojima Junzo 
Published: March 2018

SummaryAntiphospholipid antibodies (aPL) are well known to be associated with arterial and venous thrombosis. In a series of 180 patients with systemic lupus erythematosus (SLE), the prevalence of arterial thrombosis was obviously higher in the patients who had both anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) (17/35, 48.6%, p <0.05) (Table 1) than in the other patients bearing aCL or LA alone or neither of them (2/145, 1.4%). Since a substantial fraction of the former group of patients with arterial thrombosis also had thrombocytopenia (12/17, 70.6%), there was a possibility that aCL and LA might have enhanced platelet activation and aggregation. To test this possibility, we studied the in vitro effects of aCL and LA on the enhancement of platelet activation by flow cytometric analysis using anti-CD62P and anti-CD41 monoclonal antibodies directed against platelet activation-dependent granule-external membrane (PADGEM) protein and platelet glycoprotein IIb (GPIIb), respectively. Platelet activation defined by the surface expression of CD62P was not induced by aCL+·LA+ plasma only, but was significantly augmented by aCL+·LA+ plasma in combination with adenosine diphosphate (ADP) at a low concentration that had only a modest effect on platelet activation. In contrast, aCL+·LA–, aCL–·LA+ and aCL–·LA– plasma samples were incapable of enhancing platelet activation in the presence or absence of ADP stimulation. In addition to plasma samples, the purified IgG from aCL+·LA+ plasma (aCL+·LA+-IgG) also yielded apparent enhancement of platelet activation induced by ADP. Furthermore, platelet activation was generated by the mixture of aCL+·LA–-IgG and aCL–·LA+-IgG fractions prepared from individual patients, but not by each fraction alone. These results suggest that aCL and LA may cooperate to promote platelet activation, and may be involved, at least partially, in the pathogenesis of arterial thrombosis and thrombocytopenia in patients with SLE.
Antithrombotic Drugs in the Primary Medical Management of Intermittent Claudication: A Meta-analysis
Authors: Bernardi Enrico , Prins Martin , Wouter ten Cate Jan , Prandoni Paolo , Hettiarachchi Rohan , Marras Elena , Maria Stefani Piero , Girolami Antonio , Büller Harry , Girolami Bruno 
Published: March 2018

Summary
Background. There is no consensus on the efficacy of the antithrombotic drugs available for patients with intermittent claudication. Methods. A Medline and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). Mortality, cerebro- or cardiovascular events, amputations, arterial occlusions or number of revascularization procedures performed in the lower limbs, pain-free and total walking distance, ankle brachial index and calf blood flow, were the main outcomes considered. When feasible, end of treatment results, either continuous or binary, were combined with appropriate statistical methods. Results. Mortality was significantly decreased by ticlopidine compared to placebo (common odds ratio 0.68, 95% C.I., 0.49 - 0.95); clopidogrel decreased vascular events in comparison to aspirin (odds ratio 0.76, 95% C.I., 0.63 - 0.92) in level 1 studies. Arterial occlusions and the number of revascularization procedures performed were statistically significantly decreased by aspirin and ticlopidine, respectively. A small but statistically significant improvement in pain-free walking distance was determined by picotamide, indobufen, low molecular weight heparins, sulodexide and defibrotide, in small studies. Conclusions. Clopidogrel and ticlopidine do reduce clinically important events in patients with intermittent claudication and could be added to the primary medical treatment of these patients. The use of aspirin in these patients cannot be based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis, where it has documented efficacy. Other antithrombotic drugs were not properly evaluated in patients with intermittent claudication.
Prevalence of Prothrombin G20210A, Factor V G1691A (Leiden), and Methylenetetrahydrofolate Reductase (MTHFR) C677T in Seven Different Populations Determined by Multiplex Allele-specific PCR
Authors: Luhm Robert , Pearson Steven , Endean Debra , Friedman Kenneth , Montgomery Robert , Hessner Martin 
Published: March 2018

SummaryIndividuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the pro-thrombin 20210A and/or the factor V 1691A allele(s).
FXII (46C→T) Polymorphism and In Vivo Generation of FXII Activity
Authors: Kohler H. P. , Futers T. S. , Grant P. J. 
Published: March 2018

SummaryIncreased Factor XIIa concentrations have been found in association with coronary artery disease. Recently, a common 46 C to T point mutation in exon 1 of the factor XII gene has been described which is associated with lower FXII clotting activity and lower zymogen levels in relation to possession of the T allele. It is not known whether this polymorphism relates to the phenotypes of FXIIa in vivo or to coronary artery disease. The aim of the study was to investigate the interaction of this polymorphism with FXIIa plasma levels and to study the prevalence of the polymorphism in 266 patients with suspected coronary artery disease characterised by angiography and in 185 healthy controls. FXIIa levels were strongly associated with FXII genotype with lower levels with increasing numbers of T alleles (p <0.0001). There was no difference between the prevalence of this polymorphism in patients with MI compared to those without MI and controls and between all patients and controls (p ≥0.2, chi-square test). There was no association between extent of coronary artery disease (0, 1, 2, and 3 vessel disease) and FXII genotype. In conclusion, the common 46 C to T point mutation is strongly associated with FXIIa but the present study did not show an association with coronary artery disease. The role of this polymorphism in other thrombotic disorders such as ischemic stroke and venous thrombosis and its clinical significance in FXII deficient states remains to be investigated.
Fibrinogen Matsumoto III: a Variant with γ275 Arg→Cys (CGC→TGC) – Comparison of Fibrin Polymerization Properties with those of Matsumoto I (γ364 Asp→His) and Matsumoto II (γ308 Asn→Lys)
Authors: Terasawa Fumiko , Higuchi Yumiko , Ishikawa Shinsuke , Tozuka Minoru , Ishida Fumihiro , Kitano Kiyoshi , Katsuyama Tsutomu , Okumura Nobuo 
Published: March 2018

SummaryFibrinogen Matsumoto III (M-III) is a dysfibrinogen identified in a 66-year-old woman with rectal cancer. The fibrinogen level determined by the thrombin-time method was markedly decreased in preoperative coagulation tests of her plasma. Three fibrinogen polypeptide-chain gene fragments from the proposita were amplified by the polymerase chain reaction method, then sequenced. The triplet CGC encoding the amino acid residue γ275 was replaced by TGC, resulting in the substitution of Arg→Cys. There have been previous reports of nine families with the same alteration, nine families with an Arg→His variant and one family with an Arg→Ser variant in this residue, which has been shown to be one of the most important amino acids in the ’D:D’ interaction site. In addition, there are three silent mutations in the Aα-chain gene and two mutations in the intron of the Bβ-chain and the γ-chain gene. However, none of these mutations is thought to be the cause of the dysfunctional fibrinogen. The thrombin-catalyzed fibrin polymerization in the presence of 1 mM Ca ions was markedly delayed in purified M-III. Its lag period was longer than those of Matsumoto II (M-II; γ308Asn→Lys) and Matsumoto I (M-I; γ364Asp→His). γ364Asp is one of the most important residues in the polymerization pocket of the ’D:E’ interaction site and γ308Asn is located in the vicinity of a high affinity Ca2+ binding site in the D-domain, γ311-336. The maximum slope of the polymerization curve for M-III was about 4-fold steeper than that for M-I but less steep than that for M-II. These results may suggest that the tertiary structure of the polymerization pocket plays a more important role in the lateral aggregation of protofibrils than that of the ’D:D’ interaction site.
The P2Y1 Receptor Is Normal in a Patient Presenting a Severe Deficiency of ADP-induced Platelet Aggregation
Authors: Léon Catherine , Vial Catherine , Ohlmann Philippe , Hechler Béatrice , Cazenave Jean-Pierre , Lecchi Anna , Cattaneo Marco , Gachet Christian 
Published: March 2018

SummaryADP is a key stimulus inducing platelet shape change and aggregation, a rise in internal calcium and inhibition of adenylyl cyclase. These signaling pathways are thought to be activated by three independent receptors, but to date only the P2Y1 receptor responsible for calcium mobilization and the ionotropic P21 receptor have been identified. We report here the characteristics of the P2Y1 receptor in a patient presenting a selective deficiency of ADP-induced aggregation. Cloning of the P2Y1 gene revealed that the patient’s DNA and mRNA were normal. Pharmacological studies showed that the P2Y1 receptor was expressed and functional in patient’s platelets. Hence, the P2Y1 receptor is not the cause of the impaired ADP-induced platelet aggregation in this patient. The P21 mRNA was also found to be present and normal. These findings add evidence to previous observations suggesting that a third P2 receptor coupled to adenylyl cyclase may be involved in ADP-induced platelet aggregation.
Temporal and Topographic Matrix Metalloproteinase Expression after Vascular Injury in Mice
Authors: Lupu F. , Moons L. , Carmeliet P. , Goulding D. , Collen D. , Lijnen H. R. 
Published: March 2018

SummaryTemporal and topographic expression of matrix metalloproteinases (MMPs) after perivascular electric injury was studied in wild-type (WT) and urokinase-deficient (u-PA-/-) mice. Neointima formation after injury of the femoral artery was significantly reduced in u-PA-/- mice as compared to WT mice (area of 0.002 ± 0.0007 mm2 versus 0.008 ± 0.002 mm2 at 3 weeks after injury; p <0.001), associated with impaired cellular migration (nuclear cell counts of 44 ± 5 versus 82 ± 9 in cross-sectional areas; p <0.001).Zymographic and/or microscopic analysis indicated that MMP expression gradually increased to reach a maximum at 1 to 2 weeks after vascular injury. In general, MMP levels were lower in u-PA-/- than in WT mice. In non-injured arteries, MMP-2 (gelatinase A) and MMP-3 (stromelysin-1) were produced mainly by adventitial fibroblasts and/or non-contractile smooth muscle cells (SMC). One week after injury, MMP-2 and MMP-3 levels were enhanced due to an increased number and size of producing cells; 2 to 3 weeks after injury, MMP-2 and MMP-3 were produced also by some contractile SMC, which stained with α-actin antiserum. MMP-9 (gelatinase B), MMP-12 (metalloelastase) and MMP-13 (collagenase-3) were found in macrophages located mainly in the adventitia. Immunogold electron microscopic examination revealed that MMP-2 was located predominantly in association with the cell surface of fibroblasts or SMC, while MMP-9 and MMP-12 were located in well defined storage granules within macrophages. MMP-2, MMP-3 and MMP-13, but not MMP-9 or MMP-12, were also found extracellularly, associated with elastin-containing structures (MMP-2), with the basement membrane and occasionally with collagen fibres (MMP-3), or with proteoglycans, collagen and elastin (MMP-13).The temporal and topographic expression pattern of MMPs after vascular injury, coinciding with smooth muscle cell migration and neointima formation, thus is compatible with a role in vascular remodeling.
Increased Expression of Protease Activated Receptor-2 (PAR-2) in Balloon-Injured Rat Carotid Artery
Authors: D’Andrea Michael , de Garavilla Lawrence , Cheung Wai-man , Andrade-Gordon Patricia , Damiano Bruce 
Published: March 2018

SummaryProtease-induced cell signaling is mediated by specific receptors such as the emerging family of protease activated receptors (PARs). Since proteases are involved in various aspects of vascular injury, we assessed expression of PAR-2, a protease-activated receptor closely related to the thrombin receptor (PAR-1) but activated by an unknown protease, in vascular injury. Rat carotids were subjected to balloon-catheter injury and perfusion fixed at 1, 3, 7 or 14 days after injury. Sections of injured and normal carotid arteries were immunohisto-chemically labeled with a polyclonal antibody raised against the N-terminal residues 37-53 of human PAR-2. Sections were also labeled with antibodies to factor VIII-related antigen, smooth muscle actin and a proliferating cell nuclear antigen (PCNA). In normal vessels, PAR-2 labeling was diffuse and patchy in medial smooth muscle and endothelium. At one and three days after injury, before appearance of neointima, PAR-2 labeling increased in cells adjacent to damaged or necrotic smooth muscle cells. In addition, proliferating adventitial myofibroblasts labeled strongly for PAR-2. At 7 and 14 days after injury, the media and neointima of injured vessels had increased PAR-2 labeling which was most intense at the luminal edge of the neointima. Double immunohistochemical labeling confirmed the greatest expression of PAR-2 in areas with the greatest density of PCNA-positive cells. In addition, PAR-2 mRNA localization using in situ hybridization paralleled PAR-2 expression. The data suggest an upregulation of PAR-2 in response to vascular injury which is associated with medial smooth muscle damage, proliferating adventitial myofibroblasts and smooth muscle cells of the neointima, particularly those at the proliferating luminal edge of the neointima. Possible functional consequences of this receptor upregulation and its role in the response to vascular injury remain to be determined.
The Utility of Animal Models in the Preclinical Study of Interventions to Prevent Human Coronary Artery Restenosis: Analysis and Recommendations
Authors: Griggs T. R. , Badimon L. , Johnson G. J. 
Published: March 2018

SummarySmall animal models have several advantageous characteristics, but those used in preclinical restenosis research have lacked efficacy in predicting the success of interventions to inhibit restenosis in humans.Large animal models have been more successful than small animal models in predicting efficacy of interventions to inhibit restenosis in humans, but the results of studies carried out with these models have not been uniformly predictive.Confirmation of the results of small animal studies in large animals has not always yielded information predictive of success in humans; however, the absence of such confirmation has had strong negative predictive value.Small animal models used for evaluation of interventions to inhibit luminal narrowing following arterial instrumentation have failed to closely simulate human atherosclerosis and the stenotic lesions subjected to instrumentation in humans.Transgenic, atherosclerotic animals hold promise for the development of more useful small animal models to study mechanisms of the response of diseased arteries to angioplasty and stents.The pig has been the most useful large animal to study stenosis/ restenosis, but more information is needed to overcome the limitations of this model.
Increased C-reactive Protein Levels during Short-term Hormone Replacement Therapy in Healthy Postmenopausal Women
Authors: van Baal Marchien , Kenemans Peter , van der Mooren Marius , Kessel Hilda , Emeis Jef , Stehouwer Coen 
Published: March 2018

Summary
Objective: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women. Design: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks. Results: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group. Conclusion: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.
Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function
Authors: Corral J. , González-Conejero R. , Rivera J. , Ortuño F. , Aparicio P. , Vicente V. 
Published: March 2018

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.