bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperhomocysteinemia and Venous Thrombosis: A Meta-analysis
Authors: Heijer Martin den , Rosendaal Frits , Blom Henk , Gerrits Wim , Bos Gerard 
Published: March 2018

SummaryHyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease. Until the early nineties the relationship with venous thrombosis was controversial. At this moment ten case-control studies on venous thrombosis are published. We performed a meta-analysis of these reports.We performed a MEDLINE-search from 1984 through June 1997 on the keywords “homocysteine” or “hyperhomocysteinemia” and “venous thrombosis”, which yielded ten eligible case-control studies.We found a pooled estimate of the odds ratio of 2.5 (95% CI 1.8-3.5) for a fasting plasma homocysteine concentration above the 95th percentile or mean plus two standard deviations calculated from the distribution of the respective control groups. For the post-methionine increase in homocysteine concentration we found a pooled estimate of 2.6 (95% CI 1.6-4.4).These data from case-control studies support hyperhomocysteinemia as a risk factor for venous thrombosis. Further research should focus on the pathophysiology of this relationship and on the clinical effects of reducing homocysteine levels by vitamin supplementation.
No Association between the 20210 G/A Prothrombin Gene Mutation and Premature Coronary Artery Disease
Authors: Eikelboom J. W. , Parsons R. , Taylor R. R. , van Bockxmeer F. M. , Baker R. I. 
Published: March 2018

SummaryThe 20210 G/A prothrombin gene mutation is associated with an increased risk of venous thrombosis but whether there is an association of the mutation with premature coronary artery disease and acute myocardial infarction remains unclear.To further assess the role of the G/A genotype as a risk factor for arterial vascular disease, we performed a case-control study of 644 patients aged less than 50 years with angiographically proven coronary artery disease, 402 of whom had myocardial infarction, and 679 unrelated healthy control subjects aged less than 50 years, randomly selected from the electoral roll.The prevalence of the G/A genotype was 2.5% in patients with coronary artery disease, and 3.2% in control subjects (odds ratio 0.8; 95% confidence interval 0.35 to 1.83). The mutation was not more frequent among patients with a history of myocardial infarction (2.2%, odds ratio 0.7; 95% confidence interval 0.27 to 2.05), and there was no evidence of an interaction between the prothrombin mutation and conventional cardiovascular disease risk factors. There was no association between genotype and extent of angiographic coronary artery disease (p = 0.73).We conclude that the 20210 G/A prothrombin gene mutation is not a major risk factor for premature coronary artery disease in our predominantly Caucasian Australian population.
A Cross-over Pharmacokinetic Study of a Double Viral Inactivated Factor IX Concentrate (15 nm Filtration and SD) Compared to a SD Factor IX Concentrate
Authors: Peynet Jocelyne , Chambost Hervé , Négrier Claude , Briquel Marie Elisabeth , Claeyssens Ségolène , Derlon-Borel Annie , Guérois Claude , Caron Claudine , Scherrmann Jean Michel , Debray Marcel , Bridey Françoise , Goudemand Jenny 
Published: March 2018

SummaryA double blind randomized cross-over multi-center study has been conducted to compare the pharmacokinetic and coagulation activation markers of high-purity factor IX concentrate subjected to both solvent/ detergent (SD) treatment and 15 nm-filtration (FIX-SD-15) with the licensed product subjected only to solvent-detergent (FIX-SD). This filtration process allows the elimination of small particles, such as non-enveloped viruses (i.e., hepatitis A and parvovirus B19). Eleven severe hemophilia B patients (FIX coagulant activity <2 IU/dl) received one infusion of 60 IU/kg of FIX-SD and one infusion of 60 IU/kg of FIX-SD-15 at least at 10 days interval. Blood samples were obtained before and at various time up to 72 h after infusion. The decay curves of factor IX (FIX:C and FIX:Ag) were evaluated by a model independent method. Bioequivalence was found between the two concentrates using the Schuirmann test. The mean FIX:C and FIX:Ag recovery of FIX-SD-15 was 1.08 and 0.89 IU/dl/IU/kg respectively with a mean half-life of 33.3 h for FIX:C and 25.6 h for FIX:Ag. Six months after initial enrollment, pharmacokinetic parameters were similar in the 7 patients tested. There was no significant variation of prothrombin fragment 1+2 and thrombin-antithrombin complexes measured up to 6 h after infusion, indicating that there was no activation process after administration of FIX. In conclusion, these data demonstrate that the introduction of a 15 nm filtration does not alter the pharmacokinetic profile of a well characterized SD FIX concentrate while providing additional viral safety.
Inhibition of Lupus Anticoagulant Activity by Hexagonal Phase Phosphatidylethanolamine in the Presence of Prothrombin
Authors: Tannenbaum Marion , Neville Carolyn , Fortin Paul , Rauch Joyce 
Published: March 2018

SummaryWe have previously demonstrated that lupus anticoagulant antibodies from patients with systemic lupus erythematosus (SLE) specifically recognize hexagonal (II) phase phosphatidylethanolamine (PE), but not bilayer PE (Thromb Haemost 1989; 62: 892). In those studies, the involvement of proteins in this recognition was not evaluated. To address this issue, we have isolated IgG lupus anticoagulant antibodies from the plasma of SLE patients and evaluated the inhibition of lupus anticoagulant activity by hexagonal (II) phase PE in the presence and absence of purified plasma proteins. All six of the IgG lupus anticoagulant antibodies tested were inhibited by hexagonal (II) phase PE in the presence, but not the absence, of human prothrombin. In contrast, little or no inhibition was observed with prothrombin alone or with PE in combination with either β2-glycoprotein I or annexin V. These data indicate that, for certain lupus anticoagulant antibodies, inhibition by hexagonal (II) phase PE is dependent on prothrombin, suggesting that these antibodies recognize a complex of PE and prothrombin.
Activated Platelets Induce Tissue Factor Expression on Human Umbilical Vein Endothelial Cells by Ligation of CD40
Authors: Kalbas Matthias , Willuweit Antje , Henn Volker , Kroczek Richard , Müller-Berghaus Gert , Slupsky Joseph 
Published: March 2018

SummaryCD40 is a type I member of the tumour necrosis factor (TNF) receptor superfamily of proteins, and is present on a wide variety of cells including vascular endothelial cells. Ligation of this receptor on endothelial cells is known to increase expression of inflammatory adhesion molecules. We have recently demonstrated that platelets express the ligand of CD40 (CD154) within seconds of exposure to agonist, and interact with endothelial cells to participate directly in the induction of an inflammatory response. Here we show that activated platelets induce tissue factor (TF) expression on endothelial cells in a CD40/CD154-dependent manner, and that the magnitude of this response can equal that induced by TNFα. Moreover, CD40 ligation on endothelial cells downregulates the expression of thrombomodulin. We also show that CD40-mediated TF expression is less sensitive to inhibition with the oxidative radical scavenger pyrrolidine dithiocarbamate than is that mediated by TNFα, indicating that CD40 has a distinct signalling pathway. Tissue factor is a cell membrane protein which functions as the main trigger of the extrinsic pathway of blood coagulation, and its expression on endothelial cells is implicated in wound healing and angiogenesis. Since platelets are among the first cells involved in haemostasis following tissue injury, our data showing that ligation of CD40 by CD154 induces a procoagulant phenotype on vascular endothelial cells suggests that platelets may play an important role in the induction of wound healing.
Effects of Oral and Transdermal Estrogen Replacement Therapy on Markers of Coagulation, Fibrinolysis, Inflammation and Serum Lipids and Lipoproteins in Postmenopausal Women
Authors: Vehkavaara Satu , Silveira Angela , Hakala-Ala-Pietilä Tiina , Virkamäki Antti , Hovatta Outi , Hamsten Anders , Taskinen Marja-Riitta , Yki-Järvinen Hannele 
Published: March 2018

SummaryWe compared the effects of oral estradiol (2 mg), transdermal estradiol (50 g), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble Eselectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein AII concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.
Platelet Glycoprotein Receptor IIIa Polymorphism PlA1/PlA2
and Coronary Risk: a Meta-Analysis
Authors: Castelnuovo Augusto Di , Gaetano Giovanni de , Donati Maria Benedetta , Iacoviello Licia 
Published: March 2018

SummaryMembrane glycoprotein IIb/IIIa plays a major role in platelet function. The gene encoding the glycoprotein IIIa shows a common polymorphism PlA1/PlA2
that was variably associated with vascular disease. To clarify the role of PlA1/PlA2
polymorphism in coronary risk, a meta-analysis of published data was conducted. Studies were identified both by MEDLINE searches, and hand searching of journals and abstract books.A total of 34 studies for coronary artery disease (CAD), and 6 for restenosis after revascularization were identified, for a total of 9,095 cases and 12,508 controls. In CAD, the overall odds ratio for carriers of the PlA2
allele was 1.10 (95% CI: 1.03 to 1.18), and it was 1.21 (95% CI: 1.05 to 1.38) in subjects younger than 60. Overall odds ratio was 1.31 (95% CI: 1.10 to 1.56) after revascularization procedures.The association of PlA2
status with overall cardiovascular disease in the general population is significant but weak; higher risk has been identified in less heterogeneous subgroups as in the younger cohorts and in the restenosis subset with stents.
Protein Z Circulates in Plasma in a Complex with Protein Z-Dependent Protease Inhibitor
Authors: Tabatabai Amir , Fiehler Ryan , Broze George 
Published: March 2018

SummaryProtein Z (PZ) is a vitamin K-dependent plasma protein that forms a Ca++-dependent complex with factor Xa at phospholipid surfaces. This interaction between PZ and factor Xa enhances by >1000-fold the inhibition of factor Xa by the serpin called protein Z-dependent protease inhibitor (ZPI). These experiments show that PZ also binds ZPI in a process that does not require Ca++ or phospholipids. In pooled normal plasma, which contains excess ZPI relative to PZ, all the PZ appears to be bound in a complex with ZPI. The binding of PZ to ZPI reduces the rate and extent of factor XIa inhibition produced by ZPI. During the course of these studies, it was noted that a PZ purification procedure, that included NaSCN (2.0 M) elution of PZ from an immunoaffinity column, produced aggregated, inactive forms of PZ.
Studies on the Binding of 3H-SR121566, an Inhibitor of Gp IIb-IIIa Activation
Authors: Savi P. , Zamboni G. , Rescanières O. , Herbert J. M. 
Published: March 2018

SummarySR121566 is a new synthetic agent which inhibits the binding of fibrinogen to activated platelets, and platelet aggregation. 3H-SR121566 bound with nanomolar affinity (KD ranging from 45 to 72 nM) to Gp IIb-IIIa expressing cells only. On activated human platelets, this ligand allowed the detection of a maximal number of 100-140,000 binding sites. The binding of SR121566 to platelets, was displaced by several agents including RGD-containing peptides and synthetic RGD mimetics, but not by ReoPro®, a humanised monoclonal antibody which inhibits the binding of fibrinogen to the Gp IIb-IIIa complex. Neither the fibrinogen dodecapeptide nor fibrinogen itself were able to compete with SR121566 whether platelets were activated or not.Flow cytometry studies indicated that SR121566 which did not activate Gp IIb-IIIa by itself, dose-dependently prevented the detection of activation-induced binding sites on TRAP-stimulated platelets in the presence or absence of exogenous fibrinogen, indicating a direct effect on the activation state of the Gp IIb-IIIa complex. Moreover, SR121566 was able to reverse the activation of Gp IIb-IIIa and to displace the binding of fibrinogen when added up to 5 min after TRAP stimulation of platelets. When added at later times (15 to 30 min), SR121566 failed to displace fibrinogen binding, even if SR121566 binding sites were still accessible and the Gp IIb-IIIa complex not activated.In conclusion, our study is in accordance with the finding that fibrinogen is recognised by the activated Gp IIb-IIIa complex through the dodecapeptide sequence present on its gamma chain, and that this interaction is inhibited by SR121566 by preventing and reversing the activated conformation of Gp IIb-IIIa and not by direct competition with fibrinogen.
Evidence from Site-directed Mutagenesis that the Cytoplasmic Domain of the β3 Subunit Influences the Conformational State of the αvβ3 Integrin Ectodomain
Authors: Schaffner-Reckinger Elisabeth , Brons Nicolaas , Kieffer Nelly 
Published: March 2018

SummaryIn order to explore the mechanisms leading to conformational changes of the vitronectin receptor αvβ3 following ligand or divalent cation binding, we have investigated the expression of epitopes known as ligand-induced binding sites (LIBS) on 3 cytoplasmic tail mutants expressed in CHO cells. Truncation of the entire 3 cytoplasmic domain induced constitutive LIBS exposure on αvβ3 and IIb β3. Deletion of the C-terminal NITY759 sequence or disruption of the NPLY747 motif by a Y747A substitution impaired extracellular conformational changes on αvβ3 following RGDS, echistatin or Mn2+ binding, whereas the substitutions Y747F, Y759A or Y759F allowed normal LIBS exposure. Furthermore, metabolic energy depletion totally prevented Mn2+-dependent LIBS exposure, but had only a minor effect on RGDS-induced conformational changes. Our results demonstrate that the structural integrity of the NPLY747 motif in the β3 cytoplasmic domain, rather than potential phosphorylation of Tyr747 or Tyr759, is a prerequisite for conformational changes within the αvβ3 ectodo-main, and suggest that two different mechanisms are responsible for RGDS- and Mn2+-dependent conformational changes.
Influence of Contact System Deficiencies during Cardiopulmonary Bypass
Authors: Cugno Massimo , Agostini Angelo 
Published: March 2018

SummaryAs a result of the expanding indications for cardiopulmonary bypass (CPB) there is a growing number of patients undergoing this procedure who are at high surgical risk, and increasing efforts to investigate the mechanisms involved in CPB complications are warranted. Blood contact with foreign surfaces triggers systemic inflammatory response and may induce coagulation (1), this is believed to be responsible of most of the unwanted effects associated with CPB. During this procedure, contact phase activation occurs (2), involving factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK). FXII binds to negatively charged surfaces undergoing autoactivation with cleavage of Arg353-Val354 to form a two-chain molecule of 80 kD, i.e. activated FXII (FXIIa, also known as FXIIa). FXIIa can cleave PK to kallikrein which in turn cleaves FXII to produce FXIIa and a factor XII fragment of 28-30 kD (FXIIf, also known as FXIIa) and cleaves HK to HKa generating the nonapeptide bradykinin. FXIIa can cleave both FXI and PK to active enzymes, while FXIIf (which cannot bind to surfaces) cleaves PK (2) and the first component of complement (C1) (3). These mechanisms of activation differ from those initiating the coagulation cascade during in vivo haemostasis through the tissue factor pathway as a result of tissue injury (4).
Plasma Tumor Necrosis Factor α Levels and the –238* A Promoter Polymorphism in Patients with Antiphospholipid Syndrome
Authors: Bertolaccini M. L. , Lanchbury J. S. , Caliz A. R. , Katsumata K. , Vaughan R. W. , Kondeatis E. , Khamashta M. A. , Koike T. , Hughes G. R. V. , Atsumi T. 
Published: March 2018

Summary
Objectives. To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFα in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNF and disease. Patients and Method. We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFα levels were determined in plasma from 35 patients’ and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. Results. TNFα levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p 0.0001) as well as in APS patient’s group (OR 54.2 [95% CI 9.6-306.5], p 0.0001). Conclusions. Raised plasma TNFα levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFα may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNFα genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.
An Update of the Grützbalgϕ Hypothesis: The Role of Thrombosis and Coagulation in Atherosclerotic Progression
Authors: Yee Karen , Ikari Yuji , Schwartz Stephen 
Published: March 2018

SummaryWhile a great deal has been learned about the initiation of atherosclerosis, much less is known about the factors that ultimately determine progression and clinical manifestations. In this review we will focus on the possible role of coagulation, especially intramural fibrin in lesion progression.
Time and Dose Dependent Augmentation of Inhibitory Effects of Abciximab by Aspirin
Authors: Baumann Patricia , Holmes Michael , Taatjes Douglas , Sobel Burton , Schneider David 
Published: March 2018

SummaryAspirin and abciximab independently decrease the incidence of cardiac events. To identify potential interactions, antiplatelet effects of abciximab were characterized in blood from healthy subjects given aspirin. Platelet activation was determined in whole blood with and without abciximab (2 μg/ml) added in vitro. Flow cytometry was used to quantify fibrinogen binding (glycoprotein IIb-IIIa activation). Binding of fluorochrome-labeled and 125I-labeled abciximab was determined before and after exposure to aspirin. In blood from subjects given aspirin for 5 days, abciximab-induced inhibition of the capacity to bind fibrinogen in response to 1 μM ADP was greater when the daily dose had been 325 mg compared with 81 mg (% inhibition: no aspirin 53 ± 6; 81 mg daily 62 ± 5; 325 mg daily 69 ± 6). The effect of 5 daily doses of aspirin was greater than that of one. Larger single doses elicited larger effects (% inhibition 2 h after 325 mg 59 ± 6; 2 h after 650 mg 78 ± 5). Neither salicylsalicylic acid nor naproxen sodium potentiated the effect of abciximab. Exposure of platelets to 14Cacetylsalicylic acid led to acetylation of glycoprotein IIb and IIIa. Binding of 125I-abciximab to platelets was increased after 30 and 60 min. Acetylation of glycoprotein IIb-IIIa by aspirin augments inhibitory effects of abciximab in a dose- and time-dependent manner by increasing binding of abciximab to platelets.
F X Nottingham and F X Taunton Two Novel Mutations in Factor X Resulting in Loss of Functional Activity and an Interpretation Using Molecular Modelling
Authors: Srinivasan N. , Westby J. , Horn E.H. , Dolan G. , Deam S. 
Published: March 2018

SummaryWe report two novel mutations in the Factor X gene which result in a bleeding tendency in two unrelated Caucasian families. Although the mutations occur at adjacent codons in exon 8 and result in reduced functional activity with normal antigen levels, the patterns of inheritance appear to be quite distinct. Factor X Nottingham (alanine 404 threonine) appears to be associated with an autosomal recessive pattern of inheritance. In contrast, Factor X Taunton (arginine 405 glycine) results in a mode of inheritance consistent with an autosomal dominant pattern, all five of the heterozygotes in this family being clinically affected. Molecular modelling studies suggest that, in the case of Factor X Nottingham, a drastic conformational change causes major unfolding of the protein. For Factor X Taunton, less extreme conformational changes occur causing loss of functional activity such that substrate binding sites might be maintained. It is proposed that competition with wild type for substrate binding could occur leading to a dominant negative effect.
Factor V Arg306 → Gly Mutation Is not Associated with Activated Protein C Resistance and Is rare in Taiwanese Chinese
Authors: Lin Jen-Shiou , Tsay Woei , Shen Ming-Ching 
Published: March 2018

SummaryPolymerase chain reaction amplification followed by BstOI enzyme digestion and DNA sequencing was employed to detect the mutation of factor V gene. The subjects consisted of 105 venous thrombophilic patients and 183 healthy controls. Only one patient was found to have factor V Arg306 → Gly mutation, his elder son also had an identical mutation. None of the healthy subjects studied had Arg306 → Thr mutation. The rare event of factor V Arg306 → Gly mutation in patients and controls suggest that this mutation is not associated with increased risk of venous thrombosis. Conventional, modified and extended activated protein C (APC) resistance assays in this patient and his family members clearly showed that factor V Arg306 → Gly mutation is not associated with APC resistance (APC sensitivity ratio <2). In conclusion, factor V Arg306 → Gly mutation is rare in Taiwanese Chinese and not associated with APC resistance, it is possibly not a risk factor for venous thrombophilic thrombosis.