bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomised, Controlled Study of the Effects of Aerobic Exercise and Dietary Fish on Coagulation and Fibrinolytic Factors in Type 2 Diabetics
Authors: Mori Trevor , Puddey Ian , Beilin Lawrie , Burke Valerie , Morton Alan , Stanton Kim , Dunstan David 
Published: March 2018

SummaryType 2 diabetes is associated with disturbances in coagulation and fibrinolysis. Prospective studies show that increased tissue plasminogen activator (tPA) antigen increases the risk of cardiovascular mortality. The present study examined the hypothesis that combining a regime of moderate aerobic exercise with one daily fish meal as part of a low-fat diet (30% total energy) would improve coagulation and fibrinolytic factors in dyslipidaemic type 2 diabetic patients. In a randomised, controlled, 8-week trial, 55 sedentary type 2 diabetic subjects with serum triglycerides >1.8 mmol/l and/or HDL-C <1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g ω3 fatty acids/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate <100 bpm) exercise program. Plasma levels of fibrinogen, coagulation factor VIIc, tPA and plasminogen activator inhibitor (PAI-1) antigen were measured before and after intervention. In the 49 subjects who completed the study, the fish diet alone, moderate exercise alone and the combination of fish and moderate exercise all led to significant reductions in tPA antigen concentrations (-2.1 ng/ml, p = 0.02, -1.9 ng/ml, p = 0.03, -2.0 ng/ml, p = 0.01, respectively) compared to controls. In multivariate regression, changes in fasting blood glucose (positively) and erythrocyte ω3 fatty acid composition (inversely) were independent predictors of the change in tPA antigen. The fish diet alone contributed to a significant rise in coagulation factor VIIc compared to controls (4.9%, p = 0.02), which was prevented by moderate exercise. No significant effects on PAI-1 antigen and fibrinogen were seen. In view of recent epidemiological findings, the reduction in tPA antigen with both fish and moderate exercise in these dyslipidaemic type 2 diabetic patients could reflect a reduced thrombotic potential and decreased cardiovascular risk. Furthermore, a small, albeit significant, increase in coagulation factor VIIc associated with fish can be prevented by a concomitant programme of moderate exercise.
Antibodies to Factor XII Associated with Lupus Anticoagulant
Authors: Gallimore M. J. , Harris S. L. , Winter M. , Jones D. W. 
Published: March 2018

SummaryFalsely low levels of factor XII (FXII) have been documented in patients who are lupus anticoagulant positive (LA+). In addition, we have previously noted a surprisingly high incidence (20.9%) of apparently true FXII deficiency in patients who were LA+. We have hypothesised that this may be partly due to the presence of antibodies to FXII.The aim of the present study was to investigate whether LA+ patient plasmas contain antibodies directed either against FXII or FXII in association with phospholipids. Plasma samples from 60 blood donors, all LA negative, and 51 LA+ patients were tested using ELISA assays employing purified FXII, phosphatidylserine (PS) and phosphatidylethanolamine (PE). We have identified seven patients whose plasma contained either IgG or IgM that reacted with purified FXII in the absence of PS or PE. When PS was included in the assay system four additional patient plasmas were shown to contain either IgG or IgM that reacted with FXII. The plasma of one patient contained IgG that reacted with FXII both in the presence and absence of PS. There was no reactivity to FXII with either IgG or IgM when PE was included in the assay system. Affinity purified IgG from three patients whose plasma reacted with FXII in the ELISA assay in the absence of PS, gave a positive reaction in an immunoblot assay. These results suggest that FXII antibodies are present in a significant proportion of LA+ patients and may lead to an erroneous diagnosis of FXII deficiency.
Contribution of Erythrocytes to Thrombin Generation in Whole Blood
Authors: Peyrou V. , Lormeau J. C , Hérault J. P. , Gaich C. , Pfliegger A. M. , Herbert J. M. 
Published: March 2018

SummaryThrombin generation (TG) initiated by diluted tissue-factor was investigated in whole human blood, in platelet-rich plasma (PRP), in platelet-poor plasma (PPP), and in PPP supplemented with red blood cells (RBCs). TG was characterized by the lag time preceding the thrombin burst and by the endogenous thrombin potential (ETP). RBCs at normal haematocrit were found to influence the lag time to the same extent as platelets. When TG was carried out in PRP or in PPP + RBCs, both the ETP and lag time were dependent on the platelet count or on the haematocrit, but the shapes of the dose-response curves were different. The inhibition of TG in PPP+ RBCs by two direct thrombin and factor Xa inhibitors: hirudin and DX 9065A, and two antithrombin III (AT)-dependent anticoagulants: heparin and SR 90107A was found to be similar to that previously described in PPP and in PRP: hirudin and DX 9065A only delayed TG whereas heparin and SR 90107A both delayed and decreased TG. FACscan analysis following labelling with FITC-annexin V or with phycoerythrin-labelled anti-glycophorin A of samples taken in the course of TG initiated in PPP + RBCs showed that no significant haemolysis occurred and revealed that 0.51 ± 0.075% (mean ± sem, n = 3) of RBCs steadily exposed procoagulant phospholipids on their outer surface throughout the TG course. Furthermore, incubation of factors Xa and Va with washed RBCs sampled during TG in PPP +RBCs resulted in a significant and constant prothrombinase activity.Taken together, these data show for the first time that normal RBCs may participate in the haemostatic process through exposure of procoagulant phospholipids.
Hormone Replacement Therapy and Circulating ICAM-1 in Postmenopausal Women
Authors: Alhenc-Gelas Martine , Oger Emmanuel , Plu-Bureau Geneviève , Scarabin Pierre-Yves 
Published: March 2018

SummaryHormone replacement therapy may reduce the risk of coronary heart disease but underlying mechanism has not been adequately explained. Recent data suggest that intercellular adhesion molecule 1 (ICAM-1) plays a critical role in early stage of atherosclerosis and may serve as a molecular marker for the development of arterial disease. We investigated the effects of oral and transdermal cyclic oestradiol combined with progesterone on plasma concentration of soluble ICAM-1 (sICAM-1). Thirty-seven healthy postmenopausal women were randomly assigned to receive either oral estradiol valerate or transdermal estradiol both combined with micronized progesterone or no hormonal treatment. Plasma sICAM-1 was assayed at baseline and after a 6-month period. Oral but not transdermal estradiol regimen significantly decreased mean value of sICAM-1 compared with no treatment. Differences in sICAM-1 levels between active treatments were significant. There were no significant changes in mean values of fibrinogen between the three groups. Our results show a favorable effect of oral estrogen plus progesterone on a soluble marker of vascular inflammation and may provide plausible explanation for a cardioprotective effect of hormone replacement therapy among healthy postmenopausal women.
Increased Levels of Factor VIII and Fibrinogen in Patients with Venous Thrombosis Are not Caused by Acute Phase Reactions
Authors: Kamphuisen Pieter , Eikenboom Jeroen , Vos Hans , Pablo Renee , Sturk Auguste , Rosendaal Frits , Bertina Rogier 
Published: March 2018

SummaryFactor VIII activity (factor VIII:C) levels ≥150 IU/dl are associated with a 5- to 6-fold increased risk of venous thrombosis compared to levels <100 IU/dl, and fibrinogen levels ≥5.0 g/l increase the thrombosis risk 4-fold. These high levels are present in 25% resp. 3% of the patients with a first episode of venous thrombosis. These findings were based on measurements after the thrombotic event, so the factor VIII and fibrinogen levels in thrombosis patients may have been influenced by acute phase reactions or ongoing inflammatory responses. In the present study we measured plasma C-reactive protein (CRP) as a sensitive marker of an acute phase reaction in 474 thrombosis patients and 474 age- and sex-matched healthy controls, that were part of the Leiden Thrombophilia Study (LETS). Mean and median CRP levels were higher in thrombosis patients than in the controls, suggesting inflammation in some patients. CRP affected both factor VIII and fibrinogen levels, in patients and controls alike. After adjustment for the effect of CRP, high factor VIII:C levels still increased the thrombosis risk 6-fold and high fibrinogen levels 4-fold, which is for both very similar to the risk before correction for CRP levels. These results show that although systemic inflammation may be present in some of the patients, elevated levels of factor VIII:C and fibrinogen were in general not caused by acute phase reactions. This further supports a causal relationship between both high factor VIII:C and fibrinogen levels and venous thrombosis.
The Risk of Recurrent Venous Thromboembolism in Carriers and Non-carriers of the G1691A Allele in the Coagulation Factor V Gene and the G20210A Allele in the Prothrombin Gene
Authors: Schulman Sam , Sten-Linder Margareta , Wiman Björn , Egberg Nils , Johnsson Hans , Lindmarker Per ,   and the DURAC Trial Study Group
Published: March 2018

SummaryThe results concerning the risk of recurrent venous thromboembolism (VTE) in carriers of the G1691A mutation in the coagulation factor V gene are not consistent and this risk in carriers of the G20210A polymorphism in the prothrombin gene has hitherto not been reported. We followed 534 patients for 48 months after their first episode of objectively documented VTE. The prevalence of the G1691A allele in 467 (87.5%) of the patients and in 207 controls was 25.3% and 8.2%, respectively, in heterozygote form and 2.4% and 0.5%, respectively, in homozygote form. The adjusted odds ratio (OR) for the first VTE was 4.4 (95% CI 2.6-7.8). The risk of recurrent VTE in heterozygotes was not statistically different from non-carriers (17.8% vs 17.6%), with 85% power to detect a hazard ratio of 2.35. Homozygotes had a significantly increased risk (p = 0.036) of recurrent VTE. The prevalence of the G20210A allele in 456 patients and 207 controls was 6.1% and 1.4%, respectively. The adjusted OR was 4.6 (95% CI 1.6-19.3) for the first VTE in 28 carriers of this polymorphism. The risk of recurrent VTE for these was not statistically different from non-carriers with an OR of 0.9 (95% CI 0.2-2.9).
Predictive Value of Coagulation Markers Concerning Clinical Outcome 90 Days after Anterior Myocardial Infarction
Authors: Kontny Frederic , Abildgaard Ulrich , Dempfle Carl-Erik 
Published: March 2018

SummaryTo study the predictive value of coagulation markers concerning clinical outcome, prothrombin fragment F1.2 (F1.2), fibrin monomer antigen (FM), D-Dimer (DD), and fibrinogen were measured in plasma samples drawn 2 and 7 days after acute myocardial infarction (AMI) in 314 consecutive patients randomized in a clinical trial of low molecular weight heparin (Dalteparin) (the FRAMI trial). Placebo-treated patients suffering death or new AMI within 90 days had significantly higher levels at day 2 of FM (Enzymun-Test FM), and DD (TINAquant D-dimer) (p = 0.001 and 0.02, respectively), but not F1.2 (Enzygnost F1.2 micro), relative to those without serious clinical events. At day 7 all three coagulation activation markers were significantly higher in patients with subsequent adverse clinical outcome. The Dalteparin group had significantly lower levels of these markers as compared to the placebo group. Left ventricular (LV) thrombus formation was not associated with changes in coagulation activation. However, patients with thrombus had significantly higher fibrinogen levels than those without thrombus (p = 0.004 day 2), independent of treatment group. Thus, markers of coagulation activation may be useful in stratification of patients when estimating risk for adverse clinical outcome after AMI. Furthermore, elevated fibrinogen levels are associated with increased risk of LV thrombus formation.
Elevated Levels of Plasmin-α2 Antiplasmin Complexes in Unstable Angina
Authors: Bayés-Genís Antoni , Guindo Josep , Oliver Artur , Badimon Lina , Fiol Miquel , Mateo Jose , Carles Souto Joan , Dominguez Jose , Fontcuberta Jordi , Bayés de Luna Antoni 
Published: March 2018

SummaryThe evidence of elevated levels of several biochemical markers of prothrombotic state in patients with unstable angina suggests that thrombus formation and lysis play a pivotal role in acute coronary syndromes. The clinical syndrome of unstable angina encompasses a variety of clinical presentations of transient episodes of myocardial ischemia. This study was designed to assess plasmin generation in different settings of unstable angina. Evidence of plasmin generation in patients with unstable angina was measured by circulating plasmin-α2 antiplas-min complexes (PAP). A second objective was to identify whether PAP levels had a prognostic value to predict outcome. Eighty-five patients admitted to the coronary care unit for unstable angina were classified into three groups. Group A included 26 patients with postinfarction angina; group B comprised 26 patients with new onset angina; and group C included 33 patients with crescendo angina. Mean PAP levels were higher in the three groups compared to healthy controls. A significant correlation was found between levels of PAP and D-dimer, particularly in postinfarction angina (r = 0.6; p <0.0005). This trial adds new insights into the pathophysiology of unstable angina. It demonstrates that plasmin is generated in the different settings of unstable angina but particularly in postinfarction angina patients where a fibrin-rich thrombus is responsible of the symptoms. However, in this series PAP levels do not predict an uneventful outcome neither in the acute phase nor at long term (6 months).Abbreviations and acronyms: CABG: coronary artery bypass graft; CCU: coronary care unit; ECG: electrocardiogram; IABP: intraaortic balloon pump; MI: myocardial infarction; PAP: plasmin-α2 antiplasmin complexes; PTCA: percutaneous transluminal coronary angioplasty
Start of UK Confidential Haemophilia A Database: Analysis of 142 Patients by Solid Phase Fluorescent Chemical Cleavage of Mismatch
Authors: Waseem Naushin , Bagnall Richard , Green Peter , Giannelli Francesco ,   and the Haemophilia Centres
Published: March 2018

SummaryA national strategy for optimising genetic services in haemophilia A has been initiated in the UK. Solid phase fluorescent chemical cleavage of mismatch is used to screen the entire coding region of factor VIII in six segments: four amplified from the trace of mRNA in blood lymphocytes and two from genomic DNA for the 3.4 kb exon 14 and flanking intron sequences. These segments are analysed in two threefold multiplexes so that the genes of 18 patients can be screened in a single ABI 377 gel. The promoter and polyadenylation signal region are amplified and sequenced directly. We have analysed 142 unrelated patients and identified 141 factor VIII mutations and one Normandy type von Willebrand homozygote. The former mutations include 89 missense, 10 nonsense, 5 frameshift, one 24 bp deletion and one splice signal defect. These comprise 71 different changes, of which 39 have not been previously observed.
Age- and Sex-related Differences of Plasma Activated Factor VII Levels in Children
Authors: Sakata Toshiyuki , Yamamura Taku , Kario Kazuomi , Katayama Yoshiaki , Matsuyama Tatsuo , Kato Hisao , Yamamoto Akira , Miyata Toshiyuki 
Published: March 2018

SummaryAlthough the majority of factor VII (FVII) circulates in the zymogen form, low levels of activated factor VII (FVIIa) exist in plasma and play an important role in the initiation of tissue factor-induced coagulation. It has been reported that the concentrations of hemostatic components in children and adults are different. Here, we investigated the age- and sex-related differences of FVIIa and FVII antigen (FVIIag) levels in children at age of 10 (n = 123; males: n = 62; females: n = 61), and 13 (n = 105; males: n = 47; females: n = 58), and compared these levels with those of young adults (mean ± SD of age: 29.6 ± 6.0 years). In males, there was not a significant difference between the FVIIa levels of 10-year-old children and 13-year-old children, but the FVIIa levels in adult controls were significantly higher than those in children. In females, the FVIIa levels in 13-year-old children were significantly higher than that in 10-year-old children, but there was not a significant difference between 13-year-old children and adults. Thus, our study showed that plasma FVIIa levels were lower in children than in adults, and the increase of FVIIa level was earlier in females than in males.
A Common 4G Allele in the Promoter of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene as a Risk Factor for Pulmonary Embolism and Arterial Thrombosis in Hereditary Protein S Deficiency
Authors: Zöller Bengt , Frutos Pablo García de , Dahlbäck Björn 
Published: March 2018

SummaryReduced fibrinolytic capacity due to increased plasminogen activator inhibitor-1 (PAI-1) activity in plasma is a common finding in patients with coronary heart disease or venous thromboembolism, although its clinical significance is debated. Recently, a dimorphism in the PAI-1 promoter (4G-5G) has been reported and homozygosity for the 4G allele is associated with increased transcription and higher PAI-1 levels. Homozygous 4G genotype has been suggested to be a risk factor for myocardial infarction. In the present study, the 4G-5G dimorphism was determined in 349 individuals from 21 thrombophilic families with hereditary protein S deficiency and in 140 unrelated healthy controls. Among the 143 protein S deficient individuals, there was no relationship between deep or superficial venous thrombosis and the PAI-1 dimorphism. However, 26% (12/46) of individuals having protein S deficiency combined with homozygosity for the 4G allele had suffered pulmonary embolism as compared to 7% (7/97) of protein S deficient individuals carrying at least one 5G allele (p = 0.0019). In protein S deficient individuals, arterial thrombosis was found to be associated with smoking and 4G homozygosity. No association was found between the PAI-1 dimorphism and arterial or venous thromboembolism in family members without protein S deficiency. In conclusion, the PAI-1 genotype affects the phenotypic expression of thrombophilia in protein S deficient individuals.
Thrombomodulin Modulates the Mitogenic Response to Thrombin of Human Umbilical Vein Endothelial Cells
Authors: Lafay Monique , Laguna Reyes , Le Bonniec Bernard , Lasne Dominique , Aiach Martine , Rendu Francine 
Published: March 2018

SummaryThrombin interacts with its receptor and thrombomodulin on endothelial cells. We evaluated the respective roles of these two proteins on human umbilical vein endothelial cell (HUVEC) growth by comparing thrombin, S195A (a mutant thrombin in which the serine of the charge stabilizing system had been replaced by alanine), and the receptor activating peptide (TRAP). Thrombin and TRAP induced DNA synthesis (half maximal cell proliferation with 5 nM and 25 μM, respectively), whereas S195A thrombin was inactive, inferring that growth is mediated through the thrombin receptor. Surprisingly, cells stimulated by TRAP exhibited a maximal proliferation twice greater than that obtained with thrombin. Combination of thrombin and TRAP resulted in a mitogenic response higher than by thrombin alone, but lower than by TRAP alone. The role of thrombomodulin was evaluated by adding an anti-thrombomodulin antibody, which prevents formation of the thrombin-thrombomodulin complex. Antibody did not interfere with cell proliferation induced by TRAP, but enhanced that induced by thrombin. We conclude that formation of the thrombin-thrombomodulin complex restrains HUVEC proliferation mediated through the thrombin receptor.
Effect of a Synthetic Factor Xa Inhibitor, YM-60828, on Blood Vessel Patency in Combination with a Thrombolytic Agent and on Blood Loss from the Operation Site in a Rat Model of Arterial Thrombosis
Authors: Sato Kazuo , Hirayama Fukushi , Koshio Hiroyuki , Taniuchi Yuta , Matsumoto Yuzo , Kawasaki Tomihisa 
Published: March 2018

SummaryWe examined the adjunctive effect of a novel factor Xa inhibitor, YM-60828, on vessel patency and blood loss from the operation site after successful thrombolysis with a modified tissue-type plasminogen activator (moPA) in an electrically-induced carotid artery thrombosis model in rats. Five minutes after the induction of occlusive thrombus, a test drug (YM-60828, argatroban, heparin or saline) was administered by i.v. bolus injection followed by continuous infusion. Thrombolysis was induced with moPA by i.v. bolus injection at a dose of 650,000 IU/ kg. YM-60828 at 1 mg/kg i.v. followed by 3 mg/kg/h significantly prevented reocclusion, increased the duration of patency, and improved vessel patency after successful thrombolysis without any significant increase in blood loss from the operation site. Argatroban at 1 mg/kg i.v. followed by 3 mg/kg/h and heparin at 300 U/kg i.v. followed by 150 U/kg/h also significantly improved these parameters, but were accompanied by a significant increase in blood loss. These results suggest that the factor Xa inhibitor YM-60828 may be a potent and useful adjunctive agent with a lower risk of bleeding complications than argatroban and heparin in thrombolytic therapy.
A Detailed Comparison of the Performance of the Standard versus the Nijmegen Modification of the Bethesda Assay in Detecting Factor VIII:C Inhibitors in the Haemophilia A Population of Canada
Authors: Verbruggen Bert , Rivard Georges , Teitel Jerome , Walker Irwin , Giles Alan ,   Association of Hemophilia Centre Directors of Canada,   Factor VIII/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis
Published: March 2018

SummaryThe Bethesda assay is widely used to monitor the development and progress of Factor VIII:C inhibitors. Factor VIII stability in the substrate plasma (normal pool) is compromised by pH shift and reduction in protein concentration. Preliminary study, by Verbruggen and colleagues (8), suggested a reduction in spuriously positive assay results may result from buffering the normal pool plasma substrate with imidazole to pH 7.4 and substituting Factor VIII deficient plasma for imidazole buffer in the control incubation mix. These laboratory findings have now been confirmed by the performance of both the standard and the modified Bethesda assays in parallel on 877 patient samples screened during the Factor VIII:C Inhibitor Surveillance Program instituted following the conversion of all Canadian haemophilia A patients to recombinant Factor VIII. Although this study does not address the question of the clinical significance of spurious positive assays, these laboratory findings do support the conclusions of Verbruggen and the modified assay has recently been endorsed by the Factor VIII/IX Subcommittee of the SSC.