bluuebunny/crossref_metadata_2025 huggingface dataset:
La détermination et la pluralisation : l’exigence de l’uniformité référentielle
Authors: Kaneko Makoto
Published: July 2018

Il est soutenu que la détermination et la pluralisation effectuées, comme en français, au sein du DP ou du NumP, exigent l’uniformité des référents, tandis que les expressions qui servent, dans une position adjointe, à restreindre la dénotation nominale ou à préciser la pluralité des membres, comme en japonais, permettent la non-uniformité référentielle. Cette hypothèse permet de rendre compte du fait que i) une coordination nominale dénotant des membres hétérogènes peut suivre un seul démonstratif japonais, mais pas un seul déterminant français; ii) elle peut suivre un seul numéral en japonais, mais pas en français; iii) elle peut être suivie des pluriels du japonais, à la différence du pluriel flextionnel du français. Les observations suivantes viennent appuyer l’hypothèse selon laquelle les démonstratifs japonais ne sont pas des déterminants et les pluriels japonais n’incarnent pas la tête du NumP : les démonstratifs japonais ne présupposent ni l’unicité, ni la maximalité des référent(s) et peuvent suivre des modificateurs nominaux; ii) les pluriels japonais peuvent être redoublés, sont optionnels pour exprimer la pluralité, ne forcent pas l’accord au syntagme nominal et n’augmentent pas nécessairement la cardinalité de la dénotation de celui-ci.
Une famille de relatives non standard
Authors: Kupferman Lucien
Published: July 2018

Les relatives extraposées à partir de DP définis (v. Kupferman 2016) et les relatives prédicatives présentent non seulement cette caractéristique remarquable de répondre à un nombre important de réactifs distinctives semblables, mais aussi d’entrer dans un ensemble bien plus inclusif de constructions dotées de propriétés syntaxiques et interprétatives quasiment identiques. Toutes ces relatives non standard décrivent des scènes se déroulant dans une perception non agentive. Les éléments recteurs, verbes ou nominaux, de ces relatives renvoient à des prédicats qui introduisent ces scènes dans la situation. Dans une séquence formée d’un DP tête externe (« antécédent ») suivi d’une relative non standard, cette dernière fonctionne comme prédicat, et le premier comme son argument dans un système de prédication seconde. Une telle phrase complexe s’analyse ainsi sur deux niveaux : une structure argumentale de prédication seconde, et une structure syntaxique où le prédicat secondaire est projeté sous forme de relative (non standard) et l’argument secondaire sous forme de DP objet du VP primaire. L’analyse présentée veut supplanter, arguments à l’appui, la description traditionnelle d cas particulier des relatives prédicatives selon laquelle elles seraient dérivées de complétives, le complémenteur étant lui-même converti en qui sujet.
Français inclusif : conceptualisation et analyse linguistique
Authors: Alpheratz
Published: July 2018

Cet article synthétise la conceptualisation du « français, inclusif » comme ensemble de variations du français standard fondées sur, le genre et comme variété en usage dans plusieurs groupes sociaux ayant, pour point commun une conscience et/ou une politique de genre. Propre au, XXIesiècle, ce phénomène produit des observables que la recherche, linguistique peut se donner comme objet d ’étude. Sa description et sa, conceptualisation nous obligeaient à définir le cadre philosophique et la, communauté épistémique ayant présidé à son émergence mais aussi à,élaborer les outils et les termes métalinguistiques servant à son analyse.,Ainsi, « la variation diaéthique, l’épicénisation, l’écriture inclusive » ou,« double flexion partielle » et « l’hyperonymisation de genre » sont des, processus mais également de nouvelles ressources linguistiques permettant, d’étudier ces nouveaux usages. Certains énoncés peuvent relever d’une, catégorie grammaticale disparue en français : le genre neutre. Nous verrons, quelles sont les perspectives de sa réactivation et en quoi cette catégorie, grammaticale permet peut-être de répondre à un besoin que le français, standard échoue à satisfaire. Enfin, nous présenterons une introduction à,l’expérimentation linguistique du genre neutre que nous menons, et grâce à,laquelle se trouvent les instances de validation et de réfutation de, l’hypothèse de son existence et de son utilité.
Représentations envers les difficultés de la grammaire française – cas de futurs philologues polonais
Authors: Smuk Maciej
Published: July 2018

L’objectif du présent article est d’analyser les représentations se, rapportant aux difficultés de la grammaire française des étudiants en, philologie romane (études de langue et de culture françaises). Après avoir, exposé les principaux traits et les enjeux de la notion de représentation, mentale, nous présenterons et discuterons les résultats de l’étude empirique, réalisée auprès de 104 étudiants polonais, faisant leurs études à l’Institut, d’Études Romanes de l’Université de Varsovie. Durant la première étape, de la recherche, nous avons soumis à une analyse leur conscience, terminologique, celle-ci pouvant prouver une plus grande conscience du, fonctionnement de la langue. Pendant la deuxième phase, afin d’accéder, aux représentations des répondants, nous leur avons demandé de se, prononcer librement sur le degré de difficulté de divers aspects de la, grammaire française et d’expliciter les raisons de tel ou tel sentiment. Nous, avons mis l’accent, tant quant au contenu qu’à la forme, sur la perspective, qualitative et subjective. Notre recherche avait un caractère introspectif, puisant dans une approche herméneutique et phénoménologique.
Les participiales absolues sont-elles des subordonnées circonstancielles ? A propos de la sous-spécification des rapports syntaxo-sémantiques
Authors: Havu Eva , Pierrard et Michel
Published: July 2018

Les constructions participiales absolues (CPA) sont généralement réparties en deux types de constructions, selon (a) qu‘elles sont interprétées comme une structure à prédication seconde, « liée à un argument dans la prédication principale par une relation de possession » et qui « dénote une manière »(Mouret, 2011 : 51) ou (b) qu‘elles peuvent être paraphrasées par unesubordonnée circonstancielle. Nous examinerons les participiales absolues detype (b) en confrontant leurs propriétés avec celles des subordonnéescirconstancielles (SC) sur trois plans : 1. les contraintes sémantiquespesant sur l‘interprétation des prédications connectées; 2. le mode de connexionentre les prédications; 3. la caractérisation des rapports syntaxiques liant lesprédications. Notre contribution se donne pour objectif de préciser les rapportssyntaxo-sémantiques instaurés par les deux constructions (CPA et SC).
Magnesium Inhibits Platelet Activity - an Infusion Study in Healthy Volunteers
Authors: Ravn Hanne Berg , Vissinger Henrik , Kristensen Steen Dalby , Wennmalm Aake , Thygesen Kristian , Husted Steen Elkjcer
Published: July 2018

Magnesium (Mg) has shown the ability to inhibit arterial thrombus formation in some experimental animal studies. This effect may be due to an inhibition of platelet reactivity as in vitro studies have demonstrated that Mg inhibits platelet aggregation. In order to evaluate the in vivo effect of Mg in humans measurements of platelet activity, fibrinolytic activity, as well as measurements of prostacyclin (PGI2), and nitric oxide (NO) release were performed after infusion of magnesium sulphate (MgSO4) in healthy volunteers. In a placebo controlled, cross-over study in 14 healthy male subjects, 8 mmol MgSO4 was given as an intravenous bolus over 15 min followed by 3 mmol MgSO4/h.

The mean S-Mg concentration increased from 0.85 to 1.50 mM during the Mg infusion period. A transient decrease in blood pressure was observed during the initial bolus infusion of Mg. Haemodynamic parameters were otherwise stable. The bleeding time increased by 48% during the Mg infusion (p <0.005), and in accordance with this, ex vivo platelet aggregation in platelet rich plasma was significantly inhibited, both following collagen (p = 0.02) and ADP (p = 0.04) stimulation. There were no significant changes in plasma beta-thromboglobulin concentration or the excretion of 2,3-dinor-thromboxane B2 in the urine. Neither tissue plasminogen activator (t-PA)activity, tissue plasminogen activator (t-PA)antigen nor plasminogen activator inhibitor (PAI)antigen changed during the Mg infusion period. There was no sign of increased release of PGI2 from the vessel wall as judged by urinary concentration of 2,3-dinor-6-keto-prostaglandin F1α. Nor was there any sustained increase in the release of NO, measured as nitrate concentration in urine. However, a transient increase in NO release was observed during one sample period.

In conclusion a reduced platelet activity and increased bleeding time, was found during Mg infusion in healthy volunteers. Fibrinolytic activity showed no changes. An anti-platelet effect may in part be responsible for the beneficial effect of Mg, described in patients with acute myocardial infarction (MI) and preeclampsia.
Serum Thrombopoietin (TPO) Levels in Patients with Amegakaryocytic Thrombocytopenia Are much Higher than those with Immune Thrombocytopenic Purpura
Authors: Mukai Harumi Y , Kojima Hiroshi , Todokoro Kazuo , Tahara Tomoyuki , Kato Takashi , Hasegawa Yuichi , Kobayashi Toshitaka , Ninomiya Haruhiko , Nagasawa Toshiro , Abe Tsukasa
Published: July 2018

We assayed serum thrombopoietin (TPO) levels in amegakaryocytic thrombocytopenia (AMT) and immune thrombocytopenic purpura (ITP) patients by using a newly established enzyme-linked immunosorbent assay (ELISA). TPO levels in AMT patients were quite high (mean ± SD = 13.7 ± 11.2 fmoles/ml, n = 4), whereas those in ITP patients were only slightly higher (1.25 ± 0.39, n = 12) than those of the healthy donors (0.55 ± 0.2, n = 20). Furthermore, in ITP patients no correlation was observed between platelet counts and serum TPO levels (correlation coefficient = 0.14). We further assayed serum TPO levels sequentially during steroid treatment in patients with AMT and ITP. In one AMT patient serum TPO levels started to decrease in accordance with the increase of megakaryocyte counts, which preceded the increase in platelet counts. However, in ITP patients serum TPO levels did not change significantly throughout the course of the treatment despite the recovery of platelet counts. Based on these findings, we conclude that serum TPO levels may be regulated at least in part by megakaryocyte counts.
Prospective Multicenter Study on Subcutaneous Concentrated Desmopressin for Home Treatment of Patients with von Willebrand Disease and Mild or Moderate Hemophilia A
Authors: Rodeghiero Francesco , Castaman Giancarlo , Mannucci Pier Mannuccio
Published: July 2018

Desmopressin is the treatment of choice in most patients with von Willebrand disease (vWD) and mild hemophilia A (HA). Several studies have demonstrated that the intravenous and subcutaneous route of administration are equivalent in terms of pharmacokinetics and clinical efficacy. Home therapy of vWD and mild HA is desirable but so far there have been only a few case reports and no prospective studies. We report the results of a prospective study of home therapy in patients with vWD and mild-moderate HA using concentrated desmopressin self-administered subcutaneously. Clinical efficacy and safety were assessed by the patient using a questionnaire and direct interview. The patients were instructed on self-administration and dosage, reasons for treatment, recognition of side effects and recording clinical efficacy. The study lasted 12 months (range 6-17). During this time, 43/100 (43%) of the enrolled vWD patients (median basal VIII: C 24%, range 9-49) and 36/69 (52%) of HA patients (median basal VIII: C 10%, range 5-34) self-administered the drug. A total of 127 bleeding episodes requiring treatment occurred in patients with vWD and 92 in HA patients. There were 10 treatment failures of which 7 required in-hospital treatment. Overall, in 94% of treatments (excluding menorrhagia) the response was scored as excellent or good. In 86% of treated episodes of menorrhagia the response was scored as excellent or good. According to the patients, 81% of clinical situations would have required in-hospital treatment. Mild flushing, with or without headache, was the only consistent side-effect, reported in about 30% of treatments. In conclusion, home therapy with subcutaneous desmopressin for von Willebrand disease and hemophilia A was well accepted by the patients and proved feasible, efficacious and safe for the prevention or prompt treatment of bleeding.
Depletion of Intravascular Pools of Tissue Factor Pathway Inhibitor (TFPI) during Repeated or Continuous Intravenous Infusion of Heparin in Man
Authors: Hansen John-Bjarne , Sandset Per Morten , Huseby Kirsten Raanaas , Huseby Nils-Erik , Nordøy Arne
Published: July 2018

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the extrinsic coagulation system. TFPI is increased several-fold in postheparin plasma and thereby thought to contribute significantly to the antithrombotic action of heparin. The present study was conducted to investigate how repeated (n = 8) and continuous (n = 6) administration of heparin affect plasma TFPI and the inhibition of tissue factor (TF)-induced coagulation ex vivo in humans. Free TFPI antigen (TFPI Ag) increased from 19.2 ± 4.0 ng/ml to 204.7 ± 31.7 ng/ml after intravenous injection of 5000IU of unfractionated heparin. Five repeated injections of 5000 IU of heparin at 4 h intervals caused a progressive decrease (−45 ± 8%, p <0.0001 for time effect) in heparin-releasable TFPI and a progressive shortening of the clotting time as determined in a dilute prothrombin time assay (dPT) (−8.7 ± 6.1 s, p <0.0001). The basal concentration of TFPI Ag in plasma collected immediately before each heparin injection was decreased by 29 ± 15% (p <0.0001), whereas the dPT was decreased by 6.9 ± 3.5 s (p <0.0001). During a 24 h continuous infusion of heparin TFPI Ag decreased from 161.5 ± 26.0 ng/ml to 35.6 ± 4.7 ng/ml (−77.3 ± 5.1%) (p <0.0001). The contribution of TFPI to the inhibition of TF-induced coagulation during heparin infusion was estimated to decrease from 60 ± 15% to 20 ± 10% (p <0.0001). The present data indicate partial depletion of intravascular pools of TFPI by repeated and continuous heparin administration and thereby attenuation of its contribution to the antithrombotic action of heparin.
O-glycosylation of Fibrinogen from Different Mammalian Species as Revealed by the Binding of Escherichia coli Biotinylated Lectins
Authors: L’Hôte Corine , Berger Sylvie , Karamanos Yannis
Published: July 2018

After the demonstration that neither N-glycans nor neuraminic acid are involved in the binding of K88 lectins to the Bp and y chains of porcine fibrinogen and that their recognition was due to O-glycans (L’Hôte C, Berger S, Bourgerie S, Duval-Iflah Y, Julien R, Karamanos Y. Infect Immun 1995; 63: 1927-1932) it clearly appeared that these lectins could be used as probes to detect O-glycans on fibrinogens of other species. The conclusion of the present study is that many mammalian fibrinogens contain complex O-glycans on βp and γ chains. In addition, the combined use of the biotinylated K99 lectin and the Peanut agglutinin demonstrated the presence of sialylated T-antigens on the A± chains of all the fibrinogens examined. These lectins can now be used to determine differences on the glycosylation status of fibrinogens within one species and also to detect O-glycans on other glycoproteins
Factor VIII Inhibitor Antibodies with C2 Domain Specificity Are Less inhibitory to Factor VIII Complexed with von Willebrand Factor
Authors: Suzuki Suzuki , Arai Morio , Amano Kagehiro , Kagawa Kazuhiko , Fukutake Katsuyuki
Published: July 2018

In order to clarify the potential role of von Willebrand factor (vWf) in attenuating the inactivation of factor VIII (fVIII) by those antibodies with C2 domain specificity, we investigated a panel of 14 human antibodies to fVIII. Immunoblotting analysis localized light chain (C2 domain) epitopes for four cases, heavy chain (A2 domain) epitopes in five cases, while the remaining five cases were both light and heavy chains. The inhibitor titer was considerably higher for Kogenate, a recombinant fVIII concentrate, than for Haemate P, a fVIII/vWf complex concentrate, in all inhibitor plasmas that had C2 domain specificity. In five inhibitor plasmas with A2 domain specificity and in five with both A2 and C2 domain specificities, Kogenate gave titers similar to or lower than those with Haemate P. The inhibitory effect of IgG of each inhibitor plasma was then compared with recombinant fVIII and its complex with vWf. When compared to the other 10 inhibitor IgGs, IgG concentration, which inhibited 50% of fVIII activity (IC50), was remarkably higher for the fVIII/vWf complex than for fVIII in all the inhibitor IgGs that had C2 domain reactivity. Competition of inhibitor IgG and vWf for fVIII binding was observed in an ELISA system. In 10 inhibitors that had C2 domain reactivity, the dose dependent inhibition of fVIII-vWf complex formation was observed, while, in the group of inhibitors with A2 domain specificity, there was no inhibition of the complex formation except one case. We conclude that a subset of fVIII inhibitors, those that bind to C2 domain determinants, are less inhibitory to fVIII when it is complexed with vWf that binds to overlapping region in the C2 domain.
Functional Expression of Single Chain Glycoprotein lb Alpha on the Surface of COS Cells and BHK Cells
Authors: Petersen Eefke J , Posthumus Eelke , Sixma Jan J
Published: July 2018

The GpIb-IX complex constitutes the major receptor for von Wille-brand factor (vWF) on the surface of blood platelets. The vWF-binding site has been mapped to one of the three constituent chains, Gplba. Surface expression of Gplba depends on the. correct intracellular assembly with the Gplb(3 and GpIX chains. We have now grafted a portion of the extracellular domain of Gplba containing the vWF binding site onto the transmembrane/intracellular domain of the single chain surface molecule ICAM-1. Transient transfection of this chimeric protein in COS cells resulted in surface expression as assessed by immunostain-ing of live cells. Similar results were obtained after stable transfection into BHK cells. Purified vWF bound to the surface of transfected cells in the presence of ristocetin and botrocetin with a Kd of 52 ng/ml, comparable to the Kd for fixed platelets (65.5 ng/ml). This study indicates that functional expression of the vWF-binding domain of GpIbα on the surface of mammalian cells can be obtained in the absence of GpIbβ and GpIX. Furthermore, this model system simplifies existing methods for the assessment of the functional consequences of mutations in Gplba as found in pseudo-von Willebrand disease and Bemard-Soulier syndrome.
Hyperhomocysteinemia and Deep-Vein Thrombosis A Case-Control Study
Authors: Simioni Paolo , Prandoni Paolo , Burlina Alberto , Tormene Daniela , Sardella Corrado , Ferrari Vanni , Benedetti Lino , Girolami Antonio
Published: July 2018

In a case-control study, fasting total homocysteinemia was determined in 208 consecutive outpatients who underwent phlebography because of the first episode of clinically suspected deep-vein thrombosis (DVT) of lower limbs. Contrast venography confirmed the clinical suspicion in 60 patients (28.8%). Hyperhomocysteinemia was detected in 15 of the 60 patients with DVT (25.0%), and in 17 of the 148 subjects without thrombosis (11.5%; p = 0.025). The OR for having an acute DVT in patients with hyperhomocysteinemia was 2.6 (95% Cl: 1.1-5.9). It is concluded that high plasma homocysteine levels are significantly associated with DVT in symptomatic patients. Further studies are needed to clarify the clinical implications of this association.
Distribution and Activation of cAMP- and cGMP-Dependent Protein Kinases in Highly Purified Human Platelet Plasma and Intracellular Membranes
Authors: El-Daher Samer S , Eigenthaler Martin , Walter Ulrich , Furuichi Teiichi , Miyawaki Atsushi , Mikoshiba Mikoshiba , Kakkar Vijay V , Authi Kalwant S
Published: July 2018

Previously cAMP- and cGMP-dependent protein kinases (cAMP-PK, cGMP-PK) have been found predominantly associated with the particulate fraction in human platelets. We now report the distribution and activation of cAMP-PK and cGMP-PK in highly purified fractions of human platelet plasma (PM) and intracellular membranes (IM) prepared using high voltage free flow electrophoresis. Two non-hydrolys-able analogues of cAMP and cGMP namely Sp-5,6-DCl-cBiMPS and 8-p-CPT-cGMP have been used to activate cAMP-PK and cGMP-PK respectively. Addition of either agonist with [γ32P]ATP stimulated the endogenous activity of cAMP-PK or cGMP-PK in PM but not in IM. With PM Sp-5,6-DCl-cBiMPS stimulated the phosphorylation of protein substrates of Mr 16,22,24,46-50,66,90,160 and 250 kDa. A specific peptide inhibitor of cAMP-PK inhibited the phosphorylation of all of the substrates by Sp-5,6-DCl-cBiMPS. 8-pCPT-cGMP also induced the phosphorylation of a number of substrates particularly 16,22, 46-50, 90 and 250 kDa proteins. Inclusion of the cAMP-PK inhibitor peptide totally blocked the phosphorylation of the 16 and 22 kDa proteins, partially inhibited phosphorylation of 46-50 and 90 kDa proteins and had no effect on the 250 kDa protein indicating the 46-50, 90 and 250 kDa proteins were also cGMP-PK substrates. Western blotting with antibodies to cGMP-PK and the catalytic subunit of cAMP-PK revealed the presence of the kinases to be exclusively associated with PM with no detection in IM.

The presence of cAMP-PK substrates in IM was investigated by exogenous addition of catalytic subunit of cAMP-PK. Phosphoproteins of Mr 16, 22, 27, 30,45, 75,116 and 250 kDa were detected. A range of antibodies to cAMP-PK substrates were used to identify and localise the substrates. These antibodies revealed GPIb and VASP to be exclusively associated with PM fractions. Rap IB was also predominantly associated with PM with a small level detected in IM. Antibodies to the IP3 receptor (18A10 and 4C11) revealed the protein to be predominantly associated with IM. Additionally the antibody 4C11 recognised a 230 kDa protein band in PM that was not seen in IM. From the known specificity of these antibodies the results confirm the presence of a type IIP3 receptor in IM and a distinct (possible type III) IP3 receptor with the PM. the 16, 22, 27, 30, 75 and 116 kDa proteins in IM represent nwly detected substartes for camp-pk of presently unknown identity.
Comparison of the Recombinant Escherichia coli-Produced Protease Domain of Tissue-Type Plasminogen Activator with Alteplase, Reteplase and Streptokinase in a Canine Model of Coronary Artery Thrombolysis
Authors: Martin Ulrich , Kohnert Ulrich , Stern Anne , Popp Fritz , Fischer Stephan
Published: July 2018

Recent in vitro studies have shown that although recombinant Escherichia coli-produced protease domain of tissue-type plasminogen activator (t-PA) has no appreciable fibrin binding and less plasmin-forming activity compared to the wild-type, it is nevertheless an effective fibrinolytic agent in a dynamic in vitro plasma clot lysis system. The purpose of the present study was to evaluate the pharmacological profile of the protease in a canine model of coronary artery thrombosis. The effects of a single i.v. bolus injection of 1 mg/kg protease were compared with those of alteplase, reteplase and streptokinase at clinically relevant doses and dosing regimens in eight dogs per group. The protease rapidly restored coronary blood flow at 12 ± 1 min in all treated dogs with a significantly higher maximal coronary blood flow than in the reference groups, but was associated with short cycles of reocclusion in 4/8 animals. Overall, the coronary blood flow quality of the protease was not significantly different from that of the reference thrombo-lytics. Although fibrinogen was nearly completely degraded during protease treatment, the bleeding time was not significantly more prolonged than in reference groups. In conclusion, the protease domain is a rapidly acting, effective, bolus-injectable thrombolytic agent associated with a systemic lytic state and does not appear to cause significantly more bleeding than the reference thrombolytic agents.
Identification of Three Novel Mutations in Hereditary Protein S Deficiency
Authors: Bustorff Teresa C , Freire Isabel , Gago Teresa , Crespo Francisco , David Dezsö
Published: July 2018

We report the application of single-stranded conformation polymorphism (SSCP) analysis to the screening of 15 functionally important Protein S (PS) gene (PSα) regions (4.243 Kb) in 6 unrelated families with PS deficiencies. Direct sequencing of the fragments with altered migration patterns led to the identification of the corresponding molecular alterations. A missense mutation, G to T transversion at codon Cys598, and two different alterations, leading either to allelic exclusion, or premature termination of the protein translation: a G to A transition at codon Trp465 and a 1 nt (T) insertion at codon 265, were identified. The 1 nt insertion was observed in three apparently unrelated families but with a common geographical origin and the mutated allele was undetectable in platelet mRNAs of affected individuals. Family analysis confirmed, in each case, a perfect cosegregation of the mutation with the PS deficiency. We conclude that these alterations represent the causative mutations.
Haemostatic Variables in Pacific Islanders Apparently Free from Stroke and Ischaemic Heart Disease – The Kitava Study
Authors: Lindeberg Staffan , Berntorp Erik , Carlsson Roland , Eliasson Mats , Marckmann Peter
Published: July 2018

We cross-sectionally measured plasminogen activator inhibitor-1 (PAI-1) activity, fibrinogen, factor VII (FVII:C) and VIII (FVIII:C) coagulant activity, and von Willebrand factor antigen (VWF:Ag) in 162 traditional horticulturalists older than 40 years from the tropical island of Kitava, Papua New Guinea, where the intake of western food is negligible and where stroke and ischaemic heart disease appear to be absent. Identical analyses were made in Swedish subjects of comparable ages.

Kitavans had markedly lower PAI-1 activity, with 85% of males and 100% of females having PAI-1 activity ≤5 U/ml, as compared with 22 and 14% in Swedish males and females (p <0.0001). Surprisingly, Kitavans also had higher FVII:C, FVIII: C and VWF: Ag. Fibrinogen was 10% lower in Kitavan males while 25% higher in Kitavan females.

The very low PAI-1 activity in Kitavans may explain some of their apparent freedom from cardiovascular disease and probably relates to their extreme leanness.
Coagulation and Fibrinolysis Factors in Healthy Subjects Consuming High Stearic or Trans Fatty Acid Diets
Authors: Mutanen Marja , Aro Antti
Published: July 2018

The effects of stearic acid (Cl8:0) and trans fatty acids on variables related to coagulation and fibrinolysis were studied in 80 healthy humans average age 29 ± 9 years. All subjects consumed a baseline diet high in saturated fatty acids, mainly from dairy fat for 5 weeks. After this baseline diet they were allocated either to a diet high (8.7% of energy, En%) in trans fatty acids from partially hydrogenated vegetable oil (40 subjects) or a diet high (9.3 En%) in stearic acid (40 subjects) for 5 weeks. All diets contained 32.2-33.9 En% fat, 14.6-15.8 En% saturated plus trans fatty acids, 12.2-12.5 En% cis-monounsaturated and 2.9-3.5 En% polyunsaturated fatty acids and 216-250 mg/10 MJ cholesterol. The fats were mixed into solid foods and almost all daily food was provided.

In comparison with the baseline dairy fat diet no change was observed in the concentrations of plasma fibrin degradation products and D-dimers. Also the factor VII coagulant activity (F VII :C), tissue type plasminogen activity (tPA) and plasminogen activator inhibitor activity (PAI-1) were not affected by the experimental diets. Small increase in plasma fibrinogen concentration during the stearic acid diet was statistically significant (from 3.49 to 3.63 g/1; p = 0.041), but probably without any biological significance. Both diets increased plasma level of lipoprotein Lp(a). It can be concluded that as far as coagulation and fibrinolysis are concerned there is no need to differentiate between stearic acid or trans monoenoic fatty acids.
Screening for the FV: Q506 Mutation – Evaluation of Thirteen Plasma-based Methods for their Diagnostic Efficacy in Comparison with DNA Analysis
Authors: Tripodi Armando , Negri Barbara , Bertina Rogier M , Mannucci Pier Mannuccio
Published: July 2018

The factor V (FV) mutation Q506 that causes resistance to activated protein C (APC) is the genetic defect associated most frequently with venous thrombosis. The laboratory diagnosis can be made by DNA analysis or by clotting tests that measure the degree of prolongation of plasma clotting time upon addition of APC. Home-made and commercial methods are available but no comparative evaluation of their diagnostic efficacy has so far been reported. Eighty frozen coded plasma samples from carriers and non-carriers of the FV: Q506 mutation, diagnosed by DNA analysis, were sent to 8 experienced laboratories that were asked to analyze these samples in blind with their own APC resistance tests. The APTT methods were highly variable in their capacity to discriminate between carriers and non-carriers but this capacity increased dramatically when samples were diluted with FV-deficient plasma before analysis, bringing the sensitivity and specificity of these tests to 100%. The best discrimination was obtained with methods in which fibrin formation is triggered by the addition of activated factor X or Russell viper venom. In conclusion, this study provides evidence that some coagulation tests are able to distinguish carriers of the FV: Q506 mutation from non-carriers as well as the DNA test. They are inexpensive and easy to perform. Their use in large-scale clinical trials should be of help to determine the medical and economic benefits of screening healthy individuals for the mutation before they are exposed to such risk factors for venous thrombosis as surgery, pregnancy and oral contraceptives.
Selective Stimulation of Tissue-Type Plasminogen Activator (t-PA) In Vivo by Infusion of Bradykinin
Authors: Brown Nancy J , Nadeau John H , Vaughan Douglas E
Published: July 2018

Angiotensin converting inhibitors (ACEI) not only decrease angiotensin II (Ang II) but also potentiate the effects of bradykinin. Bradykinin is a potent stimulus to tissue type plasminogen activator (t-PA) secretion in animal models. In this study, we tested the hypothesis that bradykinin increases t-PA levels in humans.

Bradykinin was infused in seventeen hypertensive patients randomized to treatment with the ACEIs captopril and quinapril or with placebo. Bradykinin caused a significant decrease in mean arterial pressure (MAP) (p = 0.014) and increase in pulse (p <0.001). ACEI significantly potentiated the hemodynamic effect of bradykinin (p <0.05). Although baseline t-PA antigen levels were similar in the ACEI-treated (6.85 ± 0.85 ng/ml) and placebo-treated (7.85 ± 0.68 ng/ml) subjects, bradykinin caused a significant (p <0.01) increase in t-PA antigen levels (to 19.3 ± 8.2) only in the ACEI-treated patients. This increase in t-PA was independent of activation of the sympathetic nervous system. Bradykinin had no effect on PAI-1 antigen levels.

These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1.
Soluble Adhesion Molecules and Endothelial Cell Damage in HIV Infected Patients
Authors: Seigneur Martine , Constans Joël , Blann Andrew , Renard Martine , Pellegrin Jean Luc , Amiral Jean , Boisseau Michel , Conri Claude
Published: July 2018

Endothelial damage is present in HIV infection but our understanding of markers and mechanisms is incomplete. We found increased levels of markers of endothelial cell damage such as von Willebrand factor (vWf), soluble thrombomodulin (sTM) and adhesion molecule E- selectin in 90 subjects seropositive for HIV relative to healthy controls. sTM was strongly raised in those patients with the lowest CD4+ cell count (p <0.001), but levels of vWf increased at each incremental fall in CD4+ cell count and the two indices correlated significantly (r = -0.485, p <0.001). vWf correlated strongly with levels of the inflammatory cytokines tumor necrosis factor (TNF-α) and alpha interferon (IFN-α) but sTM correlated only weakly with IFN-α. We suggest that increased vWf is largely the result of inflammatory stimulus of the endothelium but that sTM is found only in those patients with more severe disease, and so truely represents endothelial damage.
Decrease in Factor VII Coagulant Activity during Percutaneous Transluminal Coronary Angioplasty by Heparin-Mediated Lipolytic Action
Authors: Mukherjee Manjari , Scully Michael F , Kakkar Vijay V , Philippou Helen , Lane David A , Jewitt David
Published: July 2018

Levels of factor VII coagulant activity (FVII: C) and two-chain factor Vila antigen (FVIIa: Ag) were measured in ten patients before and up to 6 h after receiving a bolus of heparin during percutaneous transluminal coronary angioplasty (PTCA). A significant and sustained post-heparin fall in the level of FVII: C was observed (approximately 30%) without any change in the level of FVIIa: Ag. The level of tissue factor antigen within the circulation remained unchanged. The observed decrease in FVII: C coincided with a significant decrease in triglyceride levels presumably due to lipoprotein and hepatic lipase released by the heparin. These findings appear to demonstrate a lipid (triglyceride) dependence of FVII: C. Thus, heparin may act indirectly as antithrombotic agent by limiting a lipid-dependent activation of the extrinsic pathway of coagulation.
The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats
Authors: van der Kaaden Marieke E , Rijken Dingeman C , Kar Kruijt J , van Berkel Theo J C , Kuiper Johan
Published: July 2018

Urokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E.coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA in rats. A preinjection of the LRP inhibitor GST-RAP reduced the maximal liver uptake of 125I-rscu-PA at 5 min after injection from 50 to 30% of the injected dose and decreased the clearance of rscu-PA from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10% of the liver uptake, respectively. The reduction in liver uptake of rscu-PA by the preinjection of GST-RAP was caused by a 91 % and 62% reduction in the uptake by parenchymal and Kupffer cells, respectively. In order to investigate the part of rscu-PA that accounted for the interaction with LRP, experiments were performed with a mutant of rscu-PA lacking residues 11-135 (= deltal25- rscu-PA). Deletion of residues 11-135 resulted in a 80% reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for respectively 60, 33 and 7% of the liver uptake of 125I-deltal25-rscu-PA. Preinjection of GST-RAP completely reduced the liver uptake of delta 125-rscu-PA and reduced its clearance to 0.79 ml/min. Treatment of isolated Kupffer cells with PI-PLC reduced the binding of rscu-PA by 40%, suggesting the involvement of the urokinase-type Plasminogen Activator Receptor (u-PAR) in the recognition of rscu-PA. Our results demonstrate that in vivo LRP is responsible for more than 90% of the parenchymal liver cell mediated uptake of rscu-PA and for 60% of the Kupffer cell interaction. It is also suggested that u-PAR is involved in the Kupffer cell recognition of rscu-PA.
Autoantibody Selectively Inhibits Binding of von Willebrand Factor to Glycoprotein Ib. Recognition Site Is Located in the A1 Loop of von Willebrand Factor
Authors: Mohri Hiroshi , Yamazaki Etsuko , Suzuki Zekou , Takano Toshikuni , Yokota Shumpei , Okubo Takao
Published: July 2018

A 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first autoantibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.
Subcutaneous Recombinant Hirudin (HBW 023) Versus Intravenous Sodium Heparin in Treatment of Established Acute Deep Vein Thrombosis of the Legs: a Multicentre Prospective Dose-ranging Randomized Trial
Authors: Schiele François , Lindgaerde Folke , Eriksson Henry , Bassand Jean-Pierre , Wallmark Anders , Hansson Per-Olaf , Grollier Gilles , Sjo Malvin , Moia Marco , Camez Anne , Smyth Vince , Walker Michael ,   for the International Multicentre Hirudin Study Group
Published: July 2018

The aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous recombinant hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 ±1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Bay 1 and Day 5±1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.
A Comparison of a Moderate with Moderate-high Intensity Oral Anticoagulant Treatment in Patients with Mechanical Heart Valve Prostheses
Authors: Pengo Vittorio , Barbero Fabio , Banzato Alberto , Garelli Elisabetta , Noventa Franco , Biasiolo Alessandro , Zasso Antonella , Volta Sergio Dalla
Published: July 2018

Background. The long-term administration of oral anticoagulants to patients with mechanical heart valve prostheses is generally accepted. However, the appropriate intensity of oral anticoagulant treatment in these patients is still controversial.

Methods and Results. From March 1991 to March 1994, patients referred to the Padova Thrombosis Center who had undergone mechanical heart valve substitution at least 6 months earlier were randomly assigned to receive oral anticoagulants at moderate intensity (target INR = 3) or moderate-high intensity (target INR = 4). Principal end points were major bleeding, thromboembolism and vascular death. Minor bleeding was a secondary end-point.

A total of 104 patients were assigned to the target 3 group and 101 to the target 4 group; they were followed for from 1.5 years to up 4.5 years (mean, 3 years). Principal end-points occurred in 13 patients in the target 3 group (4 per 100 patient-years) and in 20 patients in the target 4 group (6.9 per 100 patient-years). Major hemorrhagic events occurred in 15 patients, 4 in the target 3 group (1.2 per 100 patient-years) and 11 in the target 4 group (3.8 per 100 patient-years) (p = 0.019). The 12 recorded episodes of thromboembolism, 4 of which consisted of a visual deficit, were all transient ischemic attacks, 6 in the target 3 group (1.8 per 100 patient-years) and 6 in the target 4 group (2.1 per 100 patient- years). There were 3 vascular deaths in each group (0.9 and 1 per 100 patient-years for target 3 and target 4 groups, respectively). Minor bleeding episodes occurred 85 times (26 per 100 patient-years) in the target 3 group and 123 times (43 per 100 patient-years) in the target 4 group (p = 0.001).

Conclusions. Mechanical heart valve patients on anticoagulant treatment who had been operated on at least 6 months earlier experienced fewer bleeding complications when maintained on a moderate intensity regimen (target INR = 3) than those on a moderate-high intensity regimen (target INR = 4). The number of thromboembolic events and vascular deaths did not differ between the two groups.
Prediction of Changes in Levels of Haemostatic Variables during Natural Menstrual Cycle and Ovarian Hyperstimulation
Authors: Andersson Ola , Blombäck Margareta , Bremme Katarina , Wramsby Håkan
Published: July 2018

To find if there is a relation between levels of haemostatic variables at low and high hormonal levels (oestradiol and progesterone) in an individual, blood samples were drawn from 12 women repeatedly during one menstrual cycle (Study I) and from 14 women undergoing in vitro fertilization, before hormonal stimulation and daily during the periovu- latory period (Study II). Regression coefficients were calculated between minimum (independent) and maximum (dependent) values in both studies. In Study II highly significant regression coefficients were found between oestradiol minimum (pretreatment) and maximum (mcdian 105 and 4730 pmol/1, respectively) for coagulation factors FVIII, von Willebrand Factor (antigen), FVII (activity and antigen), fibrinogen, protein C, protein S (free), antithrombin, plasminogen and plasminogen activator inhibitor-1; furthermore, between progesterone-minimum at day -3 or -2 (related to ovum pick up) and maximum (median 4.7 and 98 nmol/1, respectively) for FVIII, von Willebrand Factor, FVII (activity and antigen), protein C, protein S (free), and plasminogen. In Study I, where much lower hormonal levels were obtained at maximum (oestradiol median 297 pmol/1 and and progesterone 47 nmol/1), the same pattern was observed especially for FVIII, FX, fibrinogen, plasminogen and plasmin inhibitor. Thus, the concentration of a haemostatic variable at a low oestradiol or progesterone level can predict the level at a high hormonal level.
Activation of the Fibrinolytic System in Patients with Coronary Artery Disease and Hyperfibrinogenemia
Authors: Stein D , Heins M , Schoebel F C , Pels K , Jax T W , Stiegler H , Reinauer H , Strauer B E , Leschke M
Published: July 2018

Elevated fibrinogen levels as well as an impaired activity of the fibrinolytic system are regarded as important cardiovascular risk factors. To elucidate a potential interrelation between fibrinogen as an indicator of a hypercoagulable state and the endogenous fibrinolytic function hemostatic and rheological as well as lipid parameters were determined in 224 consecutive patients, who underwent elective coronary angiography. In the selected study population of 81 men and 19 women with fibrinogen concentrations either ≥3.5 g/1 (n = 70) or ≤2.5 g/1 (n = 30) hyperfibrinogenemia was found to be significantly associated with increased concentrations of plasmin-α2-antiplasmin complex [PAP [median (25.-75. percentile)], 534 (361-680) μg/l vs. 289 (243-440) μg/1; p <0.001] and tissue plasminogen activator (t-PA) antigen [9 (6-11) μg/1 vs. 8 (5-9) |xg/l; p <0.05] while this association was lost in the subgroup of patients with angiographically normal coronary arteries (n = 26). In addition to these findings fibrinogen was significantly correlated with PAP (r = 0.40, p <0.001; n = 224) and t-PA antigen (r = 0.2, p <0.01; n = 224) after adjustment for age, diabetes mellitus, lipid parameters and leucocyte counts. It can be argued that elevated fibrinogen levels in patients with coronary artery disease are concomitant with an activation of the fibrinolytic system.
The Integrin α2β1 (GPIa/IIa)-I-Domain Inhibits Platelet-Collagen Interaction
Authors: Depraetere H , Wille C , Gansemans Y , Stanssens P , Lauwereys M , Baruch D , De Reys S , Deckmyn H
Published: July 2018

The integrin α2β1 is a major cellular receptor for collagen. The α2subunit contains an ± 200 amino acids inserted domain (I-domain) in the N-terminal region. A certain degree of homology exists between the I-domains found in integrins, collagen and the A-domains of vWF.

The α2-I-domain encoding region (aa residues D145 to S334) was obtained by RT-PCR from mRNA of non stimulated human PBL’s. The primers were designed to introduce the necessary restriction sites for cloning of the DNA fragment in frame downstream of the malE gene, as well as a stop codon after the last triplet. The resulting construct pMAL-c2-α2-I allows the expression of the I-domain, fused to the C-terminus of maltose binding protein (mal). The α2-I-mal is purified from the bacterial extract by affinity chromatography on an amylose column.

The purified α2-I-mal has been characterized by ELISA’s. The animal bound to immobilised collagen type I in a concentration dependent manner and could be blocked by the functional monoclonal anti-α2β1 antibody 6F1.

The interaction of α2-I-mal with collagen furthermore is Mg2+- dependent since the binding was inhibited in the presence of 10 mM EDTA or 10 mM Ca2+ but sustained in the presence of 10 mM Mg2+.

Finally, α2-I-mal itself was able to inhibit adhesion of washed platelets to collagen immobilised on a microtiterplate in a dose-dependent manner (α2-I-mal IC50:0.7 μ M) as well as platelet aggregation induced by collagen type I (α2-I-mal IC50: 0.7 μM).

With these results we could confirm that the α2-I-domain represents the collagen-binding site of α2β1 and we furthermore could indicate that this domain is able to prevent platelet adhesion to collagen and collagen-induced platelet aggregation, pointing to the primordial role of α2-I-mal and hence of α2β1 in platelet-collagen interaction.
Comparison of Dose Regimens for the Administration of Recombinant Pro-urokinase in a Canine Thrombosis Model
Authors: Burke Sandra E , Lubbers Nathan L , Nelson Richard A , Henkin Jack
Published: July 2018

Pro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radiolabelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below:

It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately by the remaining 50% given as a 30 min intravenous infusion (Group 5). At the dose used in this study, r-proUK did not produce degradation of fibrinolytic or hemostatic plasma proteins.