bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Homocysteine Reduction by B-Vitamin Supplementation on Markers of Clotting Activation
Authors: Klerk Mariska , Verhoef Petra , Verbruggen Bert , Schouten Evert , Blom Henk , Bos Gerard , den Heijer Martin 
Published: March 2018

SummaryHomocysteine may have an effect on risk of cardiovascular disease by stimulating procoagulant factors and/or impair anti-coagulant mechanisms or fibrinolysis. However, data in humans of such effects are sparse. In this intervention study, we examined the effect of homocysteine lowering by B-vitamin supplementation on prothrombin fragments 1 and 2 (F1+2), thrombin-antithrombin complex (TAT), and fibrin degradation products (D-dimer). The study comprised 118 healthy volunteers, 50 with homocysteine > 16 µmol/L and 68 with homocysteine ≤ 16 µmol/L, who were randomized to placebo or highdose B-vitamin supplements (5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine) daily for 8 weeks. Although homocysteine concentrations were 27.7% (p < 0.0001) reduced in the Bvitamin group compared to the placebo group, no effect on F1+2 and TAT concentrations was observed. A 10.4% reduction was observed for D-dimer (p = 0.08).In conclusion, it appears that in healthy subjects homocysteine reduction by B-vitamin supplementation has a modest beneficial effect on clotting activation.
Reduced Activation of the Gla19Ala FX Variant via the Extrinsic Coagulation Pathway Results in Symptomatic CRMred FX Deficiency
Authors: Pinotti M. , Marchetti G. , Baroni M. , Cinotti F. , Morfini M. , Bernardi F. 
Published: March 2018

SummaryWe characterized a symptomatic CRMred factor X (FX) deficiency produced by the Glu19Ala mutation in the γ-carboxyglutamic-rich domain. FX activity levels in plasma were markedly reduced in prothrombin time assays (< 1-5%), whereas in activated partial thromboplastin assays (16%) and in RVV assays (17%) the reduction in activity mirrored that in antigen levels (17%). Activation of recombinant 19Ala-FX by factor IXa/factor VIIIa or RVV, and the activity in thrombin generation assays, were comparable to those of wild-type FX. Differently, complete activation of recombinant 19AlaFX required a factor VIIa/TF concentration 30-fold higher than that of wild-type FX. The recombinant FVIIa significantly reduced PT values in 19Ala-FX reconstituted plasma, thus suggesting an alternative approach for treatment of FX deficiencies characterized by defective FX activation.The study of this FX deficiency provides an “in vivo” and “in vitro” model for the investigation of Gla domain interactions.
Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes
Authors: Yuksel Mehtap , Uchiba Mitsuhiro , Horiuchi Seikoh , Okabe Hiroaki , Okajima Kenji 
Published: March 2018

SummaryActivated protein C (APC), an important natural anticoagulant, inhibits tumor necrosis factor-α (TNF-α) production and attenuates various deleterious events induced by lipopolysaccharide (LPS), contributing thereby to a significant reduction of mortality in patients with severe sepsis. In this study, we investigated the mechanism(s) by which APC inhibits TNF-α production by LPS-stimulated human monocytes in vitro. Although APC inhibited LPS-induced TNF-α production in a concentration-dependent fashion, diisopropyl fluorophosphate-treated APC, an active-site-blocked APC, had no effect. APC inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. APC also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that APC inhibited LPS-induced TNF-α production by inhibiting the activation of both NF-κB and AP-1 and that the inhibitory activity of APC might depend on its serine protease activity. These results would at least partly explain the mechanism(s) by which APC reduces the tissue injury seen in animal models of sepsis and in patients with sepsis.
Ciglitazone Inhibits Plasmin-Induced Proinflammatory Monocyte Activation via Modulation of p38 MAP Kinase Activity
Authors: Syrovets Tatiana , Schüle Almut , Jendrach Marina , Büchele Berthold , Simmet Thomas 
Published: March 2018

SummaryPlasmin triggers chemotaxis and NF-κBand AP-1-mediated proinflammatory gene expression in human peripheral monocytes (PM). Compared with macrophages and dendritic cells, PM express mainly the peroxisome proliferator-activated receptor (PPAR) γ and traces of PPARα as detected by semiquantitative RT-PCR and immunoblotting. The PPARγ agonist ciglitazone, but not the PPARα agonist clofibric acid, concentration-dependently inhibited the plasmin-, but not the FMLP-induced PM chemotaxis. Similarly, release of interleukin (IL)-1α, IL-1β and tumor necrosis factor (TNF)-α from plasmin-stimulated PM was concentration-dependently inhibited by ciglitazone, but not by clofibric acid, while the LPS-induced TNF-α release remained unaffected by any of both PPAR agonists. Ciglitazone activates PPARγ as shown by a novel surface plasmon resonance analysis and inhibits the plasmin-induced activation of NF-κB and AP-1. It also inhibits p38 MAPK phosphorylation essential for the plasmin-induced PM chemotaxis and gene activation. Thus, activation of PPARγ by ciglitazone may allow controling of the plasmin-mediated recruitment and activation of PM at sites of inflammation.
Comparison of Outcomes after Hospitalization for Deep Venous Thrombosis or Pulmonary Embolism
Authors: Murin Susan , Romano Patrick , White Richard 
Published: March 2018

SummaryVenous thrombosis and pulmonary embolism are commonly viewed as different manifestations of a single disease process, venous thromboembolism. Recent evidence suggests that there may be important differences between patients who manifest these two conditions. Using linked hospital discharge records we analyzed 71,250 patients hospitalized with a principal diagnosis of venous thrombosis alone or pulmonary embolism and analyzed predictors of rehospitalization within 6 months for venous thrombosis or pulmonary embolism. There were 51233 patients diagnosed with venous thrombosis alone and 21,625 diagnosed with pulmonary embolism. Comparing patients initially diagnosed with venous thrombosis alone to patients with pulmonary embolism, the relative risk of being rehospitalized with venous thrombosis within 6 months for venous thrombosis was 2.7. Conversely, when patients with pulmonary embolism were compared to patients with venous thrombosis alone, the relative risk of rehospitalization within 6 months with a diagnosis of pulmonary embolism was 4.2. In multivariate models the strongest predictor of recurrent thromboembolism manifest as pulmonary embolism was an initial diagnosis of pulmonary embolism and the strongest predictor of recurrence as venous thrombosis was an initial diagnosis of venous thrombosis. We conclude that the initial clinical manifestation of thromboembolism strongly predicts the manifestation of a recurrence. Venous thrombosis and pulmonary embolism appear to be distinct, albeit overlapping, clinical entities with different natural histories.Presented at the International Society of Thrombosis and Haemostasis Meeting in Paris, France on July 9, 2001
Antithrombin ‘DREUX’ (Lys114Glu): A Variant with Complete Loss of Heparin Affinity
Authors: Huntington James , Conard Jacqueline , Carrell Robin , Mushunje Alec , Zhou Aiwu 
Published: March 2018

SummaryHere we report the finding of a new natural antithrombin mutation that confirms the critical contribution of lysine 114 to the binding of the core heparin pentasaccharide, with the replacement of lysine 114 by glutamate causing a complete loss in affinity. The variant was identified in a father and son, the father having been investigated for an episode of cerebral ischaemia associated with hypercholesterolaemia. The variant forms SDS-stable complexes with activated factor X (fXa) and its thermal stability and rate of factor Xa inhibition in the absence of heparin are identical to those of normal antithrombin. Normal antithrombin binds to the high affinity heparin pentasaccharide with a Kd of 1nM, as detected by a 45% change in intrinsic fluorescence, resulting in a 230-fold increase in rate of factor Xa inhibition. However, no change in fluorescence was detected for the variant when titrated with heparin or the heparin pentasaccharide, nor was there detectable activation towards factor Xa, indicating a complete loss of heparin binding.
Leukocyte trans-endothelial migration: JAMs add new pieces to the puzzle
Authors: Preissner Klaus , Santoso Sentot , Chavakis Triantafyllos 
Published: March 2018

SummaryThe molecular details of leukocyte transmigration through the endothelial barrier (also called diapedesis), which is the final step of leukocyte extravasation from the circulation to a given site of inflammation, are by far not well understood. The present review will focus on the different mechanisms potentially involved in leukocyte trans-endothelial migration. Both homophilic and heterophilic interactions between leukocyte and endothelial cell receptors will be covered, with a particular focus on the growing gene family of junctional adhesion molecules (JAM). Deciphering their mechanisms of interaction will also allow to unravel novel strategies for therapeutic intervention in inflammatory or atherothrombotic diseases.
Orthopaedic surgery in persons with haemophilia
Authors: Rodriguez-Merchan E. C. 
Published: March 2018

SummaryThe orthopaedic problems of haemophilia and the surgical techniques most frequently performed by orthopaedic surgeons on haemophilia patients are summarised in this review article. Sometimes it can be recommendable to carry out two or three orthopaedic surgical procedures in a single operative session, with the aim of solving the functional problem in a more global way, which usually is polyarticular. There is no doubt that such an undertaking implies a greater anaesthetic risk, but also avoids the repetition of surgical procedures and saves factor comsumption. Close cooperation between haematologists, orthopaedic surgeons, rehabilitation physicians, paediatricians, psychologists, physiotherapists and nurses is paramount for the satisfactory result of any orthopaedic surgical procedure. There is no doubt that continuous prophylactic clotting factor replacement (prophylactic therapy) is the optimal way to avoid the orthopaedic problems of haemophilia that can still be seen today. Until such a goal can be reached, the orthopaedic surgeon will continue performing arthrocentheses, synoviortheses, synovectomies, tendon lengthenings, débridements, osteotomies, joint replacements, osteosynthesis of fractures and other less frequent surgical procedures on persons with haemophilia.
Localization of tissue factor pathway inhibitor to lipid rafts is not required for inhibition of factor VIIa/tissue factor activity
Authors: Jack Garnet , Page Keith , Tetzloff Tina , Hall Connie , Mast Alan , Dietzen Dennis 
Published: March 2018

SummaryTissue factor pathway inhibitor (TFPI) abrogates coagulation initiated by the factor VIIa/tissue factor catalytic complex. While the gene structure of TFPI suggests that it is a secreted protein, a large pool of TFPI is associated with the vascular endothelium through its affinity for a glycosylphosphatidylinositol (GPI)-linked membrane protein. Inhibition of tissue factor by TFPI coincides with the translocation of quaternary complexes containing tissue factor, factor VIIa, factor Xa, and TFPI to detergent-insoluble plasma membrane domains rich in cholesterol, sphingomyelin, and GPI-linked proteins known as lipid rafts and caveolae. It is not known if localization of TFPI to these membrane domains is required for its inhibition of tissue factor procoagulant activity. We generated chimeric TFPI molecules linked directly to the plasma membrane via a GPI anchor or hydrophobic transmembrane domain and expressed these in HEK293 cells that produce tissue factor but not endogenous TFPI. The GPI-anchored chimera was exclusively enriched in detergent-insoluble membrane fractions while the transmembrane molecule was not. Transfectants expressing equal levels of the GPI-linked or transmembrane TFPI displayed equal anticoagulant potency as assessed by tissue factor-mediated conversion of factor X to factor Xa. Disruption of lipid rafts with cyclodextrin likewise had no effect on the inhibitory activity of the transmembrane or GPI-linked TFPI chimeras in HEK293 cells, nor on endogenous TFPI expressed by ECV304 cells. Thus, we conclude that the GPI anchor and membrane localization to lipid rafts does not enhance inhibition of factor VIIa/ tissue factor by cell-surface associated TFPI.
Peripheral artery disease in type 2 diabetes: the role of fibrinolysis
Authors: Piarulli Francesco , Sartore Giovanni , Rossetti Ciro , Martano Luigi , Carraro Paolo , De Paoli Massimo , Fedele Domenico , Lapolla Annunziata 
Published: March 2018

SummaryThe aim of the present study is to verify the relationship between peripheral artery disease (PAD) and some coagulation/fibrinolysis parameters in type 2 diabetic patients.Sixty-three type 2 diabetic patients, without PAD, were studied at baseline and after 4 years. Assessments included tissue-Plasminogen Activator (t-PA), Plasminogen Activator Inhibitor-1 antigen (PAI-1 Ag), Plasminogen Activator Inhibitor-1 activity (PAI-1 Act), Plasminogen (Pl), Fibrin peptide A (FPA), Fibrinogen (Fr), and the ankle/brachial pressure index (ABI).We observed a significant difference between diabetic patients and controls as regards tPA (11.8 ± 5.4 vs. 6.6 ± 3.0 ng/ml; p <0.05 ) and PAI-1 Act (17.8 ± 9.2 vs. 11.7 ± 6.6 ng/dl; p <0.005). After 4 years 13 diabetic patients became vasculo-pathic and, at baseline, had significantly lower tPA (8.9 ± 4.8 vs. 12.5 ± 5.3; p <0.011), and higher PAI-1 Ag (50.8 ± 22.2 vs. 32 ± 22.2; p <0.006), and PAI-1 Act values (24.1 ± 9.5 vs. 16.1 ± 8.4; p <0.014), compared with 50 diabetic patients who did not develop PAD after 4 years.These data show that the physiological equilibrium which exists between t-PA and PAI-1 moves towards higher levels in our diabetic patients compared with controls, at baseline, whereas diabetic patients who developed PAD showed a shift towards an antifibrinolytic pathway with diminished t-PA, increased PAI-1 Ag and PAI-1 Act and consequently procoagulant activity. Our study suggests that hypofibrinolysis may be involved in the future onset of PAD in type 2 diabetic patients.
Vascular endothelial growth factor (VEGF-A) plasma levels in non-small cell lung cancer: relationship with coagulation and platelet activation markers
Authors: Roselli Mario , Mineo Tommaso , Basili Stefania , Mariotti Sabrina , Martini Francesca , Bellotti Annamaria , Ambrogi Vincenzo , Spila Antonella , D’Alessandro Roberta , Gazzaniga Pier , Guadagni Fiorella , Ferroni Patrizia 
Published: March 2018

SummaryPlatelet activation, commonly found in lung cancer patients, may cause the release of angiogenic factors, such as vascular endothelial growth factor (VEGF-A). The present study was designed to investigate whether plasma VEGF-A levels were associated to different stages of non-small cell lung cancer (NSCLC). Moreover, sP-selectin, prothrombin fragment 1+2 (F1+2),thrombin-antithrombin III complex (TATc) and D-dimer levels were measured to test the hypothesis of an involvement of platelet and coagulation activation in tumor angiogenesis. VEGF-A, sP-selectin, F1+2, TATc and D-dimer levels were elevated in 65 patients with NSCLC, particularly in metastatic patients. sP-selectin (p <0.003) and F1+2 (p <0.005) levels were independently associated to VEGF-A. In addition, patients with positive levels of both sP-selectin and F1+2 had the highest levels of VEGF-A. In conclusion, our findings support the hypothesis that thrombin generation might induce platelet activation and VEGF-A release in NSCLC.
Elevation of FVIII: C in Venous Thromboembolism Is Persistent and Independent of the Acute Phase Response
Authors: Mumford Andrew , Manning Richard , Laffan Michael , O’Donnell James 
Published: March 2018

SummaryRecent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to determine whether the increased FVIII:C precedes the thrombosis or represents a secondary reactive phenomenon. In an attempt to address this question, we followed 35 patients with confirmed VTED, raised FVIII:C level (>1.5 iu/ml) and no other thrombotic tendency. Serial measurements of FVIII:C, vWF:Ag, C-reactive protein and fibrinogen were performed. We hypothesized that a persistent increase in FVIII:C in the absence of any other measures of ongoing acute phase response, would support the idea that elevation of FVIII:C is a constitutional phenomenon.Of this initial group, 94% continued to have an elevated FVIII:C level throughout the period of follow up (median 8 months; range 3 to 39 months), with no significant difference between the FVIII:C levels determined at first estimation and those obtained during follow up (p = 0.58). Conversely, only 18% had evidence of an acute phase reaction when first assessed, and nonparametric ranking analysis demonstrated no correlation between FVIII:C and either C-reactive protein or fibrinogen (p = 0.315 and 0.425 respectively).We conclude that increased FVIII:C levels following VTED are persistent, independent of the acute phase reaction, and thus may represent a constitutional risk factor for VTED.
Factor II G20210A and Factor V G1691A Gene Mutations and Peripheral Arterial Occlusive Disease
Authors: Köppel Herwig , Brodmann Marianne , Pabst Edmund , Schallmoser Katharina , Toplak Hermann , Wascher Thomas , Pilger Ernst , Renner Wilfried 
Published: March 2018

SummaryG to A mutations at positions 20210 of the prothrombin gene (F2) and 1691 of the factor V gene (F5) are established risk factors for venous thrombosis. Several factors associated with coagulation and/or fibrinolysis have been associated with arterial occlusive disease, but the role of F2 20210A and F5 1691A for arterial occlusive disease remains unclear.To investigate if F2 20210A and F5 1691A are associated with peripheral arterial occlusive disease (PAOD).We analyzed the prevalence of F2 20210A and F5 1691A alleles in 336 patients with documented PAOD at Fontaine stage II – IV and 300 controls without vascular disease. Allele frequencies in patients and controls were 0.013 and 0.022 for F2 20210A, and 0.042 and 0.045 for F5 1691, respectively, both differences being not statistically significant.Our data suggest that mutations F2 G20210A and F5 G1691A are not associated with PAOD.
Purification and Characterization of Factor VII Inhibitor Found in a Patient with Life Threatening Bleeding
Authors: Miyamoto Seiji , Iwasa Atsushi , Ishii Masao , Okajima Kenji , Kamikubo Yu-ichi 
Published: March 2018

SummaryWe recently observed a patient with acquired inhibitor-induced F.VII deficiency whose plasma level of F.VII was < 1.0%. However, the biochemical nature of the inhibitor has not yet been clarified. In the present study, we purified the F.VII inhibitor from the patient’s plasma by using activated F.VII (F.VIIa)-conjugated gel and characterized the inhibitor. The results showed that the inhibitor comprised two kinds of antibodies: one was eluted with EDTA (antibody 1) and the other with glycine-HCl buffer (pH 2.3) (antibody 2) from the F.VIIa affinity gel. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analysis of these inhibitors demonstrated that both antibodies had features of immunoglobulin G1 (IgG1) with κ and λ-light chains. Antibody 1 bound to the immobilized F.VIIa with a high affinity in the presence of calcium ion, while antibody 2 bound to the F.VIIa very weakly and the binding was independent of calcium ion. Immunoblotting analysis demonstrated that antibody 1 bound to the light chain of F.VIIa after reduction with 2-mercaptoethanol, while it did not react with either the γ carboxyglutamic acid (Gla)-domainless light chain of F.VIIa or the heavy chain with the protease domain. Antibody 1 markedly inhibited the activity of tissue factor-F.VIIa complex. Based on these observations, it is suggested that F.VIIa autoantibody (antibody 1) recognizes the calcium-dependent conformation within or near the Gla domain and inhibits F.VIIa activity by interacting with the light chain.
Thirty-three Novel Mutations in the Protein C Gene
Authors: Gandrille Sophie , Aubry Marie-Laurence , Aiach Martine , Alhenc-Gelas Martine ,   deficiencies and the French INSERM network on molecular abnormalities responsible for protein C and protein S
Published: March 2018

SummaryWe analyzed the protein C gene (PROC) with the denaturing gradient gel electrophoresis (DGGE) scanning strategy in a series of 129 patients with suspected protein C (PC) deficiency (93 with low plasma PC levels and 36 with borderline level). At least one sequence variation was found in 104 of the 129 patients. Thirty-nine sequence variations (found in 72 patients) were already reported detrimental mutations. Thirty-three were novel sequence variations, of which 19 (found in 25 patients) were probably detrimental. Five novel mutations (A1T, R9H, S11R, S12R and K193Q) were associated with qualitative plasma PC deficiency, suggesting or confirming the functional importance of amino acids at these positions. This strategy confirmed the diagnosis of inherited PC deficiency in 79/93 (84.9%) patients with low plasma PC levels and 14/36 (38.8%) patients with borderline values. In order to explain abnormal PC levels observed in patients who did not carry detrimental mutations, screening for the -1654C/T and -1641A/G PROC promoter polymorphisms known to influence plasma PC concentrations was performed. The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations.
Determination of the Putative Binding Sites for Thrombin Receptor Activating Peptide through a Hydropathic Complementary Approach
Authors: Suttnar Jiří , Dolečková Lucie , Dyr Jan 
Published: March 2018

SummaryPutative binding sites in a platelet thrombin receptor (PAR-1) for the activating peptide SFLLRNPNDKYEPF (AP) and for the bradykinin analogue MKRPPGFSPFRSSRIG were revealed using a computer program for identifying complementary peptide segments. The program is based on the assumption that interactions of agonist’s peptides and protein’s receptors can be elucidated by complementary average hydropathies as much as possible equal by size and opposite by sign. Some of the computer-found putative binding sites were close to the supposed AP-PAR-1 contacts in the amino-terminal exodomain and in the second extracellulary loop of PAR-1. Peptides complementary to these binding sites were also computer-designed and were synthesized. They mostly inhibited the aggregation of gel filtered platelets by thrombin (0.025 U/mL) with IC50 in a high micromolar range of concentrations. The peptide complementary to site L258-Y269 of PAR-1 induced aggregation of gel filtered platelets with EC50 = 98 [µmol/L] related to thrombin (0.025 U/mL) aggregation response.