bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Polymorphisms and Coronary Artery Disease in the South of France
Authors: Canavy I. , Henry M. , Morange P. E. , Tiret L. , Poirier O. , Ebagosti A. , Bory M. , Juhan-Vague I. 
Published: March 2018

SummaryVascular disease is a multifactorial disease that involves atherosclerotic and thrombotic factors. Genetic polymorphisms have been associated with myocardial infarction and angina pectoris. The aim of the present study was to assess the relationship between some genetic polymorphisms and myocardial infarction (MI) or vasospastic angina pectoris in a population from southern France. Genetic polymorphisms of the renin angiotensin system (the D/I polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor [AT1R]) and of haemostatic factors (the -675 4G/5G polymorphism of the plasminogen-activator inhibitor 1 [PAI-1] gene, and the G to T common point mutation in exon 2, codon 34 of the Factor XIII A-subunit gene) were examined.We assessed the genotype distribution in consecutive coronary artery disease (CAD) patients with MI (n = 201) and vasospastic angina pectoris (n = 43) and in 244 healthy controls comparable in age, sex, body mass index and total cholesterol level.The genotype distribution of AT1R polymorphism was significantly different between controls and patients, the prevalence of the C allele carriers being higher in patients with MI after the age of 45 than in control individuals (61 vs 45%, p <0.01), leading to an odds ratio (OR) of 2 (CI: 1.2-3.4). When looking at the group of patients with vasospastic angina the difference was even higher (76 vs 45%, p <0.01) yielding an OR of 4.3 (CI: 1.4-17.4). Genotype distributions of ACE, PAI-1 and Factor XIII polymorphisms were similar in patients and in controls.This study is in favor of a role of AT1R gene polymorphism in myocardial infarction and vasospastic angina.
Characterization of Mouse Thrombin-activatable Fibrinolysis Inhibitor
Authors: Wagenaar Gerry , Reijerkerk Arie , Tiekstra Margriet , van Rossum Agnes , Gebbink Martijn , Meijers Joost , Marx Pauline 
Published: March 2018

SummaryBased on in vitro studies, thrombin-activatable fibrinolysis inhibitor (TAFI) has been hypothesized as a link between coagulation and fibrinolysis, but the physiological role of TAFI in vivo has not yet been established. To anticipate on the availability of genetically modified mouse models, we studied the endogenous expression of TAFI in mice. Functional TAFI was found in mouse plasma. TAFI mRNA was only detectable in the liver, showing a hepatocyte-specific expression with a pericentral lobular distribution pattern. The murine TAFI cDNA was cloned and sequenced. The deduced amino acid sequence revealed that murine TAFI is highly identical to human TAFI. The murine cDNA was stably expressed and the activated recombinant protein was functionally active; it converted the substrate hippuryl-arginine, and prolonged the clot lysis time of TAFI depleted plasma. We conclude that mice have functional TAFI in plasma, which is highly similar to human TAFI. Therefore, genetically modified mice may provide useful models to study the role of TAFI in vivo.
Abbreviations: TAFI, thrombin-activatable fibrinolysis inhibitor; CPI, carboxypeptidase inhibitor from potato tubers; CPN, carboxypeptidase N; t-PA, tissue-type plasminogen activator; PPACK, H-D-Phe-Pro-Arg-chloromethylketone.
Randomized, Placebo-controlled, Blinded and Cross-matched Study on the Antiplatelet Effect of Inhaled Nitric Oxide in Healthy Volunteers
Authors: Herr Axel , Motsch Johann , Holzmann Alexandra , Weimann Jörg , Taut Friedemann , Erbe Natalie , Bode Christoph , Martin Eike , Gries André 
Published: March 2018

SummaryThe platelet inhibitory effect of 0-40 ppm inhaled nitric oxide (NO) was investigated in healthy men and women. In both groups, ADPand collagen-induced platelet aggregation was significantly inhibited 20 (T20) and 40 min (T40) after the beginning of inhalation of 5, 10, and 40 ppm. Moreover, in both men and women, the in vitro bleeding time was significantly prolonged at T20 and T40 during inhalation of 40 ppm. Inhalation of NO also inhibited P-selectin expression at 5, 10, and 40 ppm and fibrinogen binding to the GPIIb/IIIa-receptor at 40 ppm. In conclusion, in healthy volunteers, the platelet inhibitory effect of inhaled NO was not dose-related, since it was significant at 5 and 10 ppm but did not increase during the administration of higher NO concentrations. In addition, gender-related differences were only observed in ADP-induced platelet aggregation at 10 ppm and in bleeding time prolongation at 40 ppm.
An In-vitro Model to Study Device-induced Thrombosis and Embolism:
Authors: Sukavaneshvar Sivaprasad , Mohammad Syed , Solen Kenneth 
Published: March 2018

SummaryA bovine in-vitro model was developed to investigate device-induced thromboembolism (TE) and its pharmacological intervention, using a stent as a prototype device. Emboli were assessed continuously using a light-scattering microemboli detector (LSMD). Thrombus on the stent was assessed gravimetrically at the end of the experiment. The contribution of the stent as the predominant source of detectable thromboemboli in this model was verified by placing LSMD probes upstream and downstream of the stent. The effectiveness of ethylenedinitrilo-tetraacetic-acid (EDTA) and three anti-thrombogenic agents (aspirin, dipyridamole, and tirofiban) for mitigating device-induced TE was also assessed. The results show that 1) the model has potential to study device-induced TE and the efficacy of possible interventional strategies, 2) the LSMD is capable of continuous, non-invasive, real-time assessment of embolism, 3) the assessment of embolization may constitute an important part of evaluating hemocompatibility, 4) tirofiban is effective in reducing both stent-induced thrombosis and embolism above certain concentrations.
Use of the PFA-100™ Apparatus to Assess Platelet Function in Patients Undergoing PTCA during and after Infusion of cE3 Fab in the Presence of other Antiplatelet Agents
Authors: Hézard Nathalie , Metz Damien , Nazeyrollas Pierre , Droulle Chantal , Elaerts Jacques , Potron Gérard , Nguyen Philippe 
Published: March 2018

SummaryThe PFA-100™ (Dade) is a new functional whole blood analyzer, the accuracy and reliability of which have been evaluated in von Willebrand disease and during acetyl salicylate acid therapy. This new test has the advantages of rapidity and simplicity. It may be useful to monitor new antiplatelet agents, such as GPIIb/IIIa receptor antagonists. The objective of this study was to assess the PFA-100™ in comparison with aggregometry and with the percentage of blockaded receptors GPIIb/IIIa during and after c7E3 Fab infusion in fifteen patients undergoing PTCA. Our results showed a change of closure time values from normal to abnormal within a small margin of flow cytometric values (60–75% of blockaded receptors), and moreover a variable platelet response to long-term low dose aspirin treatment in agreement with aggregometry. No influence with heparin was observed. In conclusion, this study shows that PFA-100™ may be helpful in the decision making for additional antiaggregant therapy before PTCA or in monitoring long-term GPIIb/IIIa receptor antagonist treatment.
HPA-1 and HPA-3 Polymorphisms of the Platelet Fibrinogen Receptor and Coronary Artery Disease and Myocardial Infarction
Authors: Böttiger Corinna , Koch Werner , Mehilli Julinda , Seidl Holger , Schömig Kathrin , von Beckerath Nicolas , Schömig Albert , Kastrati Adnan 
Published: March 2018

SummaryPlatelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa) plays a fundamental role in atherothrombosis. The human platelet antigen (HPA) -1 and the HPA-3 are the most extensively studied polymorphisms of GPIIIa and GPIIb, respectively. This study was designed to test, in a large population, the hypothesis that these polymorphisms represent a risk factor for the occurrence of coronary artery disease (CAD) and myocardial infarction (MI).Consecutive, angiographically examined patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD (CAD, n = 998) and those with old or acute MI constituted the group with MI (MI, n = 793). As controls served subjects, matched with patients for age and sex, with neither angiographic CAD nor symptoms or signs of MI (matched controls [MC], n = 340) as well as a group of blood donors without cardiac symptoms or signs of CAD (BD, n = 104). Genotype distribution was similar across the groups; HPA-1a/a: HPA-1a/b: HPA-1b/b was 75.0%: 22.1%: 2.9% in BD, 72.6%: 24.7%: 2.6% in MC, 70.5%: 26.8%: 2.7% in CAD, and 70.7%: 26.4%: 2.9% in MI; HPA-3a/a: HPA-3a/b: HPA-3b/b was 39.4%: 40.4%: 20.2% in BD, 33.5%: 50.0%: 16.5% in MC, 35.0%: 46.4%: 17.0% in CAD, and 37.1%: 48.0%: 16.5% in MI. There was no interaction between these polymorphisms, nor between each of these polymorphisms and other risk factors.Thus, the HPA-1 and HPA-3 polymorphisms are neither separately nor in concert associated with any measurable increase of the risk for CAD or MI in angiographically evaluated subjects.
Incomplete Inhibition of Platelet Aggregation and Glycoprotein IIb-IIIa Receptor Blockade by Abciximab: Importance of Internal Pool of Glycoprotein IIb-IIIa Receptors
Authors: Pogatsa-Murray Gisela , Dickfeld Timm , Rüdiger Silja , Taubitz Winfried , Fischer Jörg , Müller Iris , Meier Dieter , Schömig Albert , Gawaz Meinrad , Ruf Andreas , Patscheke Heinrich 
Published: March 2018

SummaryResting platelets contain a substantial internal pool of GPIIb-IIIa complexes that is exposed on the surface of activated platelets. Whether the exposure of internal GPIIb-IIIa complexes on the activated platelet surface affects therapy with GPIIb-IIIa antagonists is poorly understood. We addressed this issue in thirteen patients who underwent elective coronary stenting and received abciximab. Platelet aggregation, surface expression of GPIIb-IIIa and P-selectin, receptor blockade of GPIIb-IIIa, and platelet release in response to ADP and thrombin-receptor activating peptide (TRAP) were determined ex vivo by Lumi-aggregometry and flow cytometry before, during and after abciximab administration. We found that inhibition of aggregation and GPIIb-IIIa blockade of ADP-stimulated platelets was almost complete during abciximab administration. In contrast, when TRAP was used to stimulate platelets ex vivo aggregation was only partially inhibited, most likely due to release of internal pool of unblocked GPIIb-IIIa complexes. Using electron microscopy we found that 7E3-occupied GPIIb-IIIa complexes are internalized into the surface connected system (SCS) and the α-granules of washed platelets which was associated with a reduced degranulation of the α-granula membrane protein P-selectin. We conclude, that despite internalization of abciximab into the internal pool of GPIIb-IIIa, upon strong platelet activation with thrombin a significant amount of unblocked internal GPIIb-IIIa can be exposed on the platelet surface and mediate platelet aggregation. Incomplete blockade of the internal GPIIb-IIIa pool may limit clinical efficacy of abciximab.
Treatment with Interferon plus Ribavirin in anti-HIV Negative Patients with Congenital Coagulation Disorders and Chronic Hepatitis C
Authors: Sauleda Silvia , Altisent Carmen , Puig Lluís , Esteban Rafael , Guardia Jaume , Esteban Juan 
Published: March 2018

SummaryHepatitis C virus (HCV) infected hemophiliacs respond at low rate to interferon (IFN) monotherapy.To assess efficacy of IFN and RBV in HIV negative hemophiliacs with chronic hepatitis C and identify early predictive factors of response.Twenty naive patients were treated with interferon and RBV for twelve months. Response was assessed by both serial ALT and HCV RNA levels.Normalization of ALT with clearance of HCV RNA occurred in seven (35%) patients. Age and age at infection were the only features associated with a higher likelihood of response. In all responders the viral load had decreased by at least one log within two months of starting treatment.Combination of interferon and ribavirin is well tolerated by hemophiliacs who achieve similar sustained response rates to non-hemophiliacs. Quantitative assessment of viral load at two months of treatment is a useful method to identify non-responders at an early stage.
Sucrose Formulated Recombinant Human Antihemophilic Factor VIII Is Safe and Efficacious for Treatment of Hemophilia A in Home Therapy
Authors: Gorina E. , Kellermann E. , Vosburgh E. , Abshire T. C. , Brackmann H.-H. , Scharrer I. , Hoots K. , Gazengel C. , Powell J. S. ,   and the International Kogenate-FS Study Group
Published: March 2018

SummaryTo add an increased level of safety to antihemophilic factor replacement therapy, a full-length, recombinant Factor VIII (rFVIII) product has been developed without human-derived plasma proteins during purification and formulation and using an additional solvent/detergent viral inactivation step. This first clinical trial of a sucrose-formulated full-length rFVIII (rFVIII-FS) was conducted in previously treated patients (≥100 prior exposure days) with severe (<2% FVIII) hemophilia A in North America (NA) and Europe (EU). Pharmacokinetic profiles for rFVIII-FS were compared with those of currently licensed rFVIII product (Kogenate®) in 35 patients. Safety and efficacy during home therapy were evaluated in 71 patients. The new formulation displayed a pharmacokinetic profile similar to that of rFVIII. Patients on home therapy received a cumulative total of 11,867 exposure days, 12,546 infusions, and 22,443,694 IU of rFVIII-FS. Of 2585 bleeds, 93.5% were treated with 1-2 infusions and 80.5% of responses were rated as excellent or good. No evidence of de novo inhibitor formation was observed. Only 0.27% of infusions were associated with any drugrelated adverse event. Except for an episode of intermittent chest pain with palpitations which ceased after treatment with analgesics, associated adverse events were mild or moderate. Overall, rFVIII-FS provided excellent hemostatic control, was well-tolerated, and caused no significant adverse effects, thus demonstrating safety and efficacy for treatment of bleeds in patients with hemophilia A.
Relationship between Factor VIII Mutation Type and Inhibitor Development in a Cohort of Previously Untreated Patients Treated with Recombinant Factor VIII (Recombinate™)
Authors: Williams Ian , Bray Gordon , Peake Ian , Goodeve Anne ,   for the Recombinate™ PUP Study Group
Published: March 2018

SummaryA cohort of 79 previously untreated patients (PUPs) with moderatesevere haemophilia A (baseline Factor VIII <2%) were enrolled in a study to evaluate the safety, efficacy and immunogenicity of recombinant factor VIII (r-FVIII, Recombinate™). Blood samples were obtained retrospectively from a total 55 PUPs who were investigated for the spectrum of FVIII gene mutations responsible for their haemophilia. FVIII gene inversion mutations were found in 27 (49%) patients. Two patients had partial gene deletions. The remaining 26 patients were then screened for mutations in the FVIII gene coding region using conformation sensitive gel electrophoresis. Point mutations were identified in 22 (85%) of the patients and 14 of these mutations were novel. Study subjects were monitored for the development of FVIII inhibitors throughout the study. A total of 23 of the 73 evaluable subjects (including one subject with a low inhibitor titer at baseline) demonstrated an inhibitor on one or more occasions; 11 (15%) were persistent. Inhibitors were detected in patients with partial gene deletions and inversions and in three of eight patients with missense mutations. No inhibitors were found in 11 patients with small insertions or deletions resulting in an alteration of the protein translation reading frame (frameshift mutations). The results corroborate the observation that mutation type is an important determinant of the propensity to develop inhibitory anti-FVIII antibody.
A Monoclonal Antibody Raised against Human β-factor XIIa which also Recognizes α-factor XIIa but not Factor XII or Complexes of Factor XIIa with C1 Esterase Inhibitor
Authors: Esnouf M. , Burgess Annette , Dodds Alister , Sarphie Anna , Miller George 
Published: March 2018

SummaryA monoclonal antibody (mAb 2/215) against human β-factor XIIa (β-FXIIa), was shown by equilibrium binding studies to have a high affinity for α-factor XIIa (α-FXIIa) (Kd 1.8 nM) and β-FXIIa (Kd 0.65 nM) but no detectable reaction with FXII zymogen or α - esterase inhibitor (C1-INH) complex. Surface plasmon resonance studies showed that the mAb 2/215 bound to immobilized α-FXIIa with high affinity (KD 3.93 ± 1.46 × 10−11 M). Western blots employing mAb 2/215 indicated that human plasma contained small amounts of α-FXIIa but no β-FXIIa. mAb 2/215 did not inhibit the amidolytic activity of β-FXIIa and protected β-FXIIa from inhibition by C1-INH. The recovery by ELISA ,employing mAb 2/215 as the capture antibody, of α-FXIIa added to plasma was 11.3%, 42% after inhibition of α-FXIIa with 3:4dichloroisocoumarin, and 82% when 0.5% TritonX100 was added to the assay. Gel filtration showed that the majority of plasma α-FXIIa existed as a complex (Mr ∼170000). This distinctive mAb increases the capacity to study the contact system in health and disease.
Hereditary Thrombocytopenia due to Reduced Platelet Production
Authors: Tonelli Roberto , Strippoli Pierluigi , Grossi Alberto , Savoia Anna , Iolascon Achille , Savino Maria , Teriaca Maria , Servedio Veronica , Morfini Massimo , Zelante Leopoldo , Borgna-Pignatti Caterina , Rosito Pasquale , Pession Andrea , Paolucci Guido , Bagnara Gian 
Published: March 2018

SummaryHereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/ c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.
Expression of Vascular Endothelial Growth Factor in Human Umbilical Vein Endothelial Cells Stimulated with Interleukin-1α
Authors: Itaya Hiroyuki , Nasu Satoki , Yoshida Hidemi , Matsubara Yuki , Fujimoto Koji , Matsumiya Tomoh , Kimura Hiroto , Satoh Kei , Imaizumi Tadaatsu 
Published: March 2018

SummaryVascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells. We studied the production of VEGF by human umbilical vein endothelial cells (HUVEC) and smooth muscle cells (SMC) in response to the stimulation with interleukin-1α (IL-1α). HUVEC expressed VEGF mRNA in response to IL-1α in doseand time-dependent manners. In HUVEC VEGF protein was detected only in cell lysates whereas in SMC most of the VEGF protein was detected in the conditioned medium. Immunofluorescent staining also confirmed the cell-associated VEGF in HUVEC. IL-1α also induced the expression of mRNA for IL-1α itself in HUVEC. Cycloheximide treatment of HUVEC slightly inhibited the IL-1α-induced expression of VEGF mRNA, and IL-1α may mediate, at least in part, VEGF expression in response to IL-1α. The growth of HUVEC stimulated with IL-1α was inhibited by a neutralizing antibody against VEGF. We conclude that IL-1α and VEGF may play an important role in autocrine growth regulation of HUVEC.
CD9 Gene Deficiency Does not Affect Smooth Muscle Cell Migration and Neointima Formation after Vascular Injury in Mice
Authors: Lupu F. , Collen D. , Le Naour F. , Boucheix C. , Lijnen H. R. 
Published: March 2018

SummaryThe hypothesis that CD9, a member of the tetraspanin family, plays a role in smooth muscle cell (SMC) migration was tested with the use of a vascular injury model in wild-type (CD9+/+) and CD9-deficient (CD9−/−) mice. Neointima formation 3 weeks after electric injury of the femoral artery was not significantly different in CD9+/+ and CD9−/− mice (area of 0.019 ± 0.0034 mm2 versus 0.013 ± 0.0036 mm2; mean ± SEM, n = 6). The medial areas were also comparable, resulting in intima/media ratio’s of 1.3 ± 0.15 and 0.90 ± 0.22, respectively. Nuclear cell counts in cross-sectional areas of the injured region were comparable in media (33 ± 5 versus 27 ± 2) and neointima (135 ± 16 versus 97 ± 17) of CD9+/+ and CD9−/− arteries. Immunocytochemical analysis revealed expression of CD9 in the endothelium, by SMC in the media and by some fibroblasts in the adventitia of non-injured femoral arteries. Three weeks after injury, there appeared to be a gradient of increased CD9 expression from the adventitia to the neointima, in which SMC are abundantly present. Immunogold labeling and electron microscopy with non-injured femoral arteries of CD9+/+ mice confirmed the presence of CD9 at the surface of adventitial fibroblasts and in SMC or pericytes, as well as in the endothelium.Thus, in this model CD9 is highly expressed by migrating SMC, but deficiency of CD9 does not affect SMC migration or neointima formation after perivascular injury.
Characterization of a Monoclonal Antibody, D73H, that Maps to a Highly Conserved Region on Fibrinogen Bβ Chain
Authors: Rybarczyk B. J. , Pereira M. , Simpson-Haidaris P. J. 
Published: March 2018

SummaryThe primary structure of fibrinogen is highly conserved across species, yet often times monoclonal antibodies produced against the fibrinogen of one species will not crossreact with the fibrinogen of another. Herein, we describe the production and characterization of murine MAb, D73H, raised against human fibrinogen. D73H crossreacts with a highly conserved epitope on the Bβ chain of fibrinogen from human, rat, bovine, guinea pig, and mouse. Western blotting revealed that D73H reacted with the Bβ chain of plasmin fragment D, localizing its epitope to Bβ134-461. A 7 kDa band was identified by D73H in Western blots of reduced fibrinogen CNBr-fragments. N-terminal sequencing mapped this fragment to Bβ243-253, further localizing the epitope to Bβ243-305. In silico analysis indicated that Bβ243-305 is predominantly hydrophilic, and surface probability prediction indicated three potential antigenic determinants corresponding to Bβ252-258, Bβ262-269, and Bβ279-286. Further in silico analysis of the crystal structure of fibrinogen fragment D-D indicated that Bβ262-269 (FGRKWDPY) is predominantly α-helical and located on the surface of the molecule adjacent to a bend imposed in the β chain at residue 260, which is near the junction between the rigid coiled-coil domain and the globular C-terminus. A synthetic peptide corresponding to Bβ261-272 competitively inhibited the binding of D73H to the Bβ chain of denatured intact fibrinogen and reduced and denatured Bβ chain in Western blots, experimentally proving the validity of these predictive algorithms. Together these data indicate that, although plasmin resistant, Bβ chain residues Bβ261-272 comprising the D73H epitope are highly conserved across species, surface exposed, and immunogenic.