bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin resistance: an atherothrombotic syndrome
Authors: Freeman Mark , Mansfield Michael , Barrett Jenny , Grant Peter 
Published: March 2018

SummaryThe insulin resistance syndrome (IRS) is a clustering of atherothrombotic traits associated with increased vascular risk. We investigated the degree to which the phenotypic correlations between these traits are due to shared genetic and environmental factors.A multivariate genetic analysis was performed in 537 adults from 89 healthy white north European families. All traits showed significant heritability. BMI had significant genetic correlations with fasting insulin, systolic blood pressure (sBP), plasminogen activator activator inhibitor-1 (PAI-1) and fibrinogen and triglyceride. Fasting insulin had a significant genetic correlation with fibrinogen and triglyceride and Factor VII (FVII). Significant genetic correlations were shown between triglyceride and PAI-1, fibrinogen and FVII. PAI-1 and tissue plasminogen activator (t-PA) showed significant genetic correlation with sBP and with each other. Pleiotropy was demonstrated between fibrino-gen and PAI-1, t-PA and FVII. Significant environmental correlations were also demonstrated.This study demonstrates pleiotropy between coagulation and fibrinolytic factors. Shared genetic and environmental factors influencing haemostatic, metabolic and anthropometric traits underlie the atherothrombotic nature of the IRS.
A Common Polymorphism Flanking the ATG Initiator Codon of GPIbα Does not Affect Expression and Is not a Major Risk Factor for Arterial Thrombosis
Authors: Corral J. , Lozano M. L. , González-Conejero R. , Martínez C. , Iniesta J. A. , Rivera J. , Vicente V. 
Published: March 2018

SummaryThe platelet membrane glycoprotein (GP) Ibα plays a key role in the initial formation of thrombi. Polymorphisms (VNTR and HPA-2) in this receptor are associated with increased risk of coronary heart disease (CHD) and cerebral vascular disease (CVD). We investigated whether a recently described polymorphism (S/R), due to a single base change (T → C) five nucleotides upstream the initiator codon of GPIbα, might influence the expression of the protein, and be implicated in the development of arterial thrombosis.One hundred and thirty nine healthy individuals provided blood samples for DNA analysis of platelet GPIbα polymorphisms, and for flow cytometric analysis of the surface expression of the receptor. A group of 20 S/R normal individuals and an identical number of S/S participants, age and sex matched, was investigated for the analysis of the density of various platelet receptors. The distribution of the S/R polymorphism was also analyzed in two case/control studies including 104 CVD patients, 101 CHD patients, and one control age, sex, and environmental risk factors matched for each case patient. Surface density of GPIbα showed no wide variations between individuals, was not influenced by the presence of S or R alleles, nor associated with the VNTR or HPA-2 polymorphisms. The prevalence of the S/R genotype among CVD and CHD patients was not distinct from that in the control groups. We conclude that the S/R polymorphism of GPIbα, flanking the initiator codon of the receptor, does not seem to be associated with surface levels of the protein, and is not an independent risk factor for arterial thrombosis.
Screening for Autoimmune Markers Is Unnecessary during Follow-up of Adults with Autoimmune Thrombocytopenic Purpura and no Autoimmune Markers at Onset
Authors: Vantelon J. M. , Godeau B. , André C. , Bierling P. 
Published: March 2018

SummaryIn an attempt to evaluate the frequency of autoimmune markers in autoimmune thrombocytopenic purpura (AITP) and to determine if autoimmune markers in patients with isolated AITP were associated with particular disease manifestations, we analyzed records of 122 consecutive adults with AITP. Twenty-nine patients (24%) had significant titers of one or several autoimmune markers at AITP onset. Among them, 16 (13%) had antinuclear antibodies. The presence of autoimmune markers did not correlate with presenting feature, response to treatment or long-term outcome of AITP. Six patients (5%) developed seven autoimmune diseases during follow-up, comprising systemic lupus erythematosus, an antiphospholipid syndrome, autoimmune haemolytic anemia (n = 2), Grave’s disease, Hashimoto’s disease and primary biliary cirrhosis. At AITP onset, three of these patients had isolated biological markers of the autoimmune disease they later developed. The annual average incidence rate of autoimmune diseases was 1% per patient-year in the entire group and 0.4% in the group of patients with no autoimmune markers at AITP onset. This low rate is probably due to careful assessment at diagnosis for concomitant overt autoimmune disease. We recommend extensive screening for autoimmune markers at AITP onset, and careful follow-up of patients with autoimmune markers. Routine screening for autoimmune markers during AITP follow-up is not necessary for patients with no autoimmune markers at AITP onset.Systemic lupus erythematosus (SLE) and other autoimmune disorders can complicate autoimmune thrombocytopenic purpura (AITP) or be diagnosed concomitantly with otherwise unremarkable AITP (1, 2). However, the frequency and prognostic value of isolated autoimmune markers (i. e. not associated with an autoimmune disorder), particularly antinuclear antibodies (ANA) at AITP onset or during follow-up is controversial (3-8). For example, the committee organized by George et al. (9) to write guideline on the diagnosis and treatment of AITP stated that the search for ANA and lupus anticoagulant were of “uncertain appropriateness at diagnosis and during follow-up”. In an attempt to help practicians to make decisions, we analyzed the frequency of autoimmune markers and autoimmune disorders at onset and during the follow-up in 122 adults with AITP and no overt autoimmune disease at diagnosis. These consecutive patients were followed by the same physician for a mean period of 6 years, and had routine screening tests for autoimmune markers and disorders at onset, before steroid therapy, and regularly during follow-up.
Fluvastatin Decreases Soluble Thrombomodulin in Cardiac Transplant Recipients
Authors: Aillaud Marie-Françoise , Habib Gilbert , Kreitmann Bernard , Métras Dominique , Luccioni Roger , Bouvenot Gilles , Juhan-Vague Irène , Ambrosi Pierre 
Published: March 2018

SummaryWe conducted a randomized, placebo controlled, double-blind, cross-over study, to assess the effects of a 4-week fluvastatin therapy on plasma markers of endothelial activation or injury in 20 transplanted heart recipients. The levels of thrombomodulin and von Willebrand factor antigen were higher at baseline in cardiac transplant recipients than in age and sex-matched healthy controls. Plasma total cholesterol showed a 21% reduction on fluvastatin therapy (p = 0.0001). Fluvastatin treatment had no significant effect on creatininemia, plasma cyclosporine, PAI-1 antigen, PAI-1 activity, tPA antigen, and Von Willebrand factor. However, fluvastatin produced a significant decrease of plasma thrombomodulin (66.7 ng/ml on placebo versus 58.8 ng/ml on fluvastatin, p <0.001), suggesting a rapid improvement of endothelial injury in these patients.
The Management of Oral Anticoagulant Therapy: The Patient’s Point of View
Authors: Barcellona Doris , Contu Paolo , Sorano Gian , Pengo Vittorio , Marongiu Francesco 
Published: March 2018

SummaryThe aims of this study were to investigate on the general adhesion of the patients to oral anticoagulant therapy, and particularly on the quality of life of our patients, the doctor-patient relationship and the Centre-patient relationship. For this purpose we administered a questionnaire containing 17 main questions each with a maximum of 4 secondary questions. The questionnaire was administered to two groups of 127 and 137 oral anticoagulated patients (127 males and 137 females, mean age 55 ± 19 years), followed at two Anticoagulation Clinics, in two Italian cities, Cagliari (Sardinia) and Padua (North East Italy). The cities differed in the number of patients monitored and the management modalities of anticoagulation. The results show that oral anticoagulant therapy does not limit the life-style of the patients. Only 11% of the patients complain of limitations to their daily life. Fifty-two percent believe their health has improved, and 87% are not afraid of negative consequences. The doctor-patient relationship is considered very important by 96% of patients. Seventy-eight percent refer to the Anticoagulation Clinic also for other health problems, 93% consider it important to be assessed by the doctor at the Anticoagulation Clinic, while 83% believe the doctor should always hand out the results personally. We conclude that in general oral anticoagulant therapy is accepted by the majority of patients, in spite of the need for periodic monitoring. The doctor-patient relationship should be taken into account, even in the case of a monitored, computer-assisted method of dose-adjustment.
Characterization of Transgenic Mice that Secrete Functional Human Protein C Inhibitor into the Circulation
Authors: van Vuuren A. , Girma Merone , Tiekstra Margriet , Kwast Liane , Koster Johanna , Rijneveld Anita , Elisen Marc , van der Poll Tom , Meijers Joost , Wagenaar Gerry 
Published: March 2018

SummaryProtein C inhibitor (PCI) is a heparin binding serine protease inhibitor in plasma, which exerts procoagulant activity by inhibiting thrombomodulinbound thrombin or activated protein C (APC). Since the role of PCI in vivo is largely unknown we generated genetically modified mice with expression of human PCI mRNA in hepatocytes only. Three transgenic lines have been characterized. Transgenic mice did not show gross developmental abnormalities. Two lines showed a pericentral and one line showed a periportal expression pattern of human PCI mRNA in the liver. Genetically modified mice secreted a functional transgenic protein into the circulation (3-5 µg/ml plasma in heterozygous mice and 10 µg/ml in homozygous mice), which inhibited human APC activity in the presence of heparin. Interestingly, transgenic mice in which human PCI was expressed periportally in the liver had the highest specific activity. Endogenous mouse PCI mRNA could only be detected in the male and female reproductive system, but not in the liver, indicating that endogenous PCI levels in the circulation are low or even absent in mice. These results demonstrate that the human PCI transgenic mice are a suitable model for studying the in vivo role of PCI in blood coagulation.
Platelets Release their Lysosomal Content In Vivo in Humans upon Activation
Authors: Ciferri Silvia , Emiliani Carla , Guglielmini Giuseppe , Orlacchio Antonio , Nenci Giuseppe , Gresele Paolo 
Published: March 2018

SummaryPlatelets contain, besides α- and δ-granules, lysosomes which store glycohydrolases able to degrade glycoproteins, glycolipids and glycosaminoglycans. While several studies have shown that α- and δ-granule secretion takes place “in vivo” in humans upon platelet activation, no data are available on the “in vivo” release of lysosomes. We have studied the release of platelet lysosomal contents “in vivo” in healthy volunteers at a localized site of platelet activation by measuring markers of lysosomal secretion in the blood oozing from a skin wound inflicted for the measurement of the bleeding-time. The levels of β-N-acetylhexosaminidase (Hex) were 13.1 ± 0.85 mU/ml in bleedingtime blood and 10.2 ± 0.66 mU/ml in plasma (p <0.001). Hex in serum was 16.4 ± 0.72 mU/ml. The levels of β-galactosidase were also higher in bleeding-time blood than in plasma (0.85 ± 0.07 mU/ml vs 0.4 ± 0.05 mU/ml, p <0.001). In bleeding-time blood collected at one minute intervals, Hex rose progressively consistent with ongoing platelet activation and flow-cytometry showed a progressive increase of the expression of LIMP and LAMP-2, two lysosomal associated proteins. In conclusion, our data demonstrate that platelet lysosomal glycohydrolases are released “in vivo” in humans upon platelet activation.
Hypofibrinogenaemia with Compound Heterozygosity for Two γ Chain Mutations – γ 82 Ala→Gly and an Intron Two GT→AT Splice Site Mutation
Authors: Wyatt Jane , May Stephen , George Peter , Brennan Stephen 
Published: March 2018

SummaryWe investigated the molecular basis of hypofibrinogenaemia in a woman with a history of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains. However careful inspection of reverse phase chain separation profiles showed apparent homozygosity for a more hydrophilic form of the γ chain. DNA Sequencing showed only heterozygosity for a CGT→GGT (Ala→Gly) mutation at codon γ82, but further sequencing showed an additional GT splice sequence mutation at the 5’ end of intron 2 of the γ gene. Translation of mRNA containing this intron would result in premature truncation explaining the phenotypic homozygosity of the γ82 Ala→Gly substitution. The patient’s sister had a mild bleeding disorder with hypofibrinogenaemia and she too was a compound heterozygote for the γ mutations. Her nephew had only the novel splice site mutation, while her mother and daughter inherited only the γ82 Ala→Gly substitution.
Use of a New Monoclonal Antibody-Based Enzyme Immunoassay for Soluble Fibrin to Exclude Pulmonary Embolism
Authors: Sanson Bernd-Jan , de Monyé Wouter , Lijmer Jeroen , Huisman Menno , Büller Harry , Nieuwenhuizen Willem , Brandjes Dees P. , Mac Gillavry Melvin ,   the ANTELOPE-Study Group
Published: March 2018

SummaryWe prospectively evaluated the diagnostic performance of a new soluble fibrin assay in 303 consecutive patients with suspected pulmonary embolism and examined potentially useful cut-off levels at which this disease can be safely excluded. In addition, the diagnostic accuracy was calculated in the subgroups of in- and outpatients. The ROC curve of the assay in the total study cohort had an area under the curve of 0.69. The cut-off level associated with a sensitivity and negative predictive value of 100% was 20 ng/ml, but the specificity was only 4%. The cut-off level with a sensitivity of 90% was 30 ng/ml, which corresponded with a specificity and negative predictive value of 27% and 86%, respectively. The diagnostic performance was comparable in the subgroups of in- and outpatients. We conclude that the soluble fibrin assay has a low diagnostic accuracy and seems unsuitable as a screening test for the exclusion of pulmonary embolism.
Factor Xa Acts as a PDGF-Independent Mitogen in Human Vascular Smooth Muscle Cells
Authors: Braun Marina , Fischer Annett , Wittpoth Michael , Glusa Erika , Schrör Karsten , Bretschneider Ellen 
Published: March 2018

SummaryThis study investigates the mitogenic effect of the coagulation factor Xa in smooth muscle cells (SMC) from human saphenous vein and the procoagulant activity of these cells. Factor Xa elicited a concentrationdependent increase in [3H]thymidine incorporation. This mitogenic effect of factor Xa was inhibited by DX-9065a and BABCH, indicating the requirement of proteolytic activity of the enzyme. Factor Xa activated the MAP kinases ERK1/2 concentration-and time-dependently. PDGF-neutralizing antibodies neither inhibited the increase in [3H]thymidine incorporation nor ERK-1/2 phosphorylation in factor Xa-stimulated cells, suggesting that factor Xa-induced signaling and mitogenic activity in human venous SMC are independent of PDGF. Exposure of SMC to recalcified plasma resulted in a significant thrombin generation which was inhibited by anti-tissue factor antibody, tissue factor pathway inhibitor, inactivated factor VIIa and DX-9065a. These data indicate that interaction of SMC with the clotting system may contribute to venous graft disease, i.e. thrombus formation and intimal hyperplasia.
TERIMA-2: National Extension of Thrombolytic Treatment with Recombinant Streptokinase in Acute Myocardial Infarct in Cuba
Authors: Marrero-Miragaya María ,   The TERIMA Group of Investigators
Published: March 2018

Summary
Aim: The extension of recombinant streptokinase (rSK) use in Cuba and to evaluate its effect on in-hospital mortality of patients with acute myocardial infarct (AMI). Methods: A phase IV clinical study was performed in 52 hospitals from the 14 Cuban provinces. Patients (any age) with ST segment elevation or bundle branch block were included if they came less than 12 h after the onset of AMI symptoms, without contraindications for thrombolytic therapy. They received 1.5 × 106 IU of rSK (Heberkinasa, Heberbiotec, Havana) intravenously, during one hour. Endpoints were death due to cardiac (pump failure, wall rupture, arrhythmia) or any cause and cardiovascular events at hospital release. Results: The study included 2923 patients, 22 – 98 years-old, 74.4% men, which represented 37.2% of the total AMI patients attended at the participating hospitals from November 1992 to May 1995. Aspirin was given to 92.5% and betablockers to 65.3%. AMI was confirmed in 93.5% of the patients. The mean symptoms – rSK infusion time interval was 5.25 h (22.3% of the patients treated within the first 3 h). 302 patients died, 80.1% of them due to cardiac causes, 12 attributed to rSK treatment, and 16 to non-cardiac causes. This 10.4% mortality represents a 4% absolute and a 28.3% relative reduction (179 lives saved per year) as compared to a survey made before rSK treatment was introduced. In a logistic regression analysis, mortality was favored by age, symptoms – infusion time, Killip class, and not having taken aspirin or betablockers. Feminine gender was close to the limit of significance. The more frequent adverse events were arrhythmias and hypotension during infusion. Major bleeding occurred in 27 patients (9 strokes). Conclusion: Local recombinant-DNA biotechnology can influence on a major health problem with favorable cost/ and risk/ benefit balances, not possible in a developing country with an imported drug. The further extension of this treatment in the country is feasible and recommended, monitored through an appropriate pharmacosurveillance program.
Short-term Prognostic Value of Lipid Measurements in Patients with Angina pectoris
Authors: Bolibar Ignasi , Assmann Gerd , Thompson Simon , von Eckardstein Arnold ,   The ECAT Angina Pectoris Study Group
Published: March 2018

SummaryWe studied the role of various markers of lipid metabolism, hemostasis and inflammation in a two year follow-up of 3000 patients with angina pectoris, during which time 106 patients experienced myocardial infarction or sudden coronary death. Low levels of high density lipoprotein (HDL) cholesterol and of apolipoprotein (apo) A-I were most strongly associated with increased coronary risk. The relative risk per standard deviation increase was 0.68 for HDL cholesterol (95% confidence interval 0.55 to 0.84) and 0.66 for apoA-I (0.54 to 0.81). These associations were independent of other coronary risk factors, other lipid measurements, hemostatic factors, and C-reactive protein (CRP). The associations of total and LDL cholesterol, triglycerides, apoB, and lipoprotein(a) with coronary events were not independent of HDL cholesterol or hemostatic factors. We conclude that HDL cholesterol or apoA-I, hemostatic risk factors, and CRP are important prognostic markers of coronary events in secondary prevention.
Unopposed Estrogen Increases Total Plasma Factor VII, but not Active Factor VII
Authors: de Valk-de Roo Gerdien , Emeis Jef , Nicolaas-Merkus Ans , Netelenbos Coen , Stehouwer Coen D. 
Published: March 2018

SummaryEstrogen therapy may increase the risk of arterial thromboembolism, at least in the short term. In a randomized, double-blind and placebocontrolled study in 25 healthy postmenopausal women (52.5 ± 2.8 years), we therefore examined the short-term effect of unopposed estrogen on the fasting and fat-load-stimulated plasma levels of total factor VII versus active factor VII. Plasma total factor VII was measured by use of a chromogenic assay; plasma active FVII by a recently developed method using truncated tissue factor. As compared to placebo, 8 weeks of oral 17β-estradiol (2 mg daily) increased the mean fasting and postprandial plasma levels of total factor VII by 17 and 21% points, respectively (both P < 0.01), but did not affect the fasting and/or postprandial plasma levels of active factor VII (mean change both 0.05 ng/mL; P > 0.35). Furthermore, the change in the fasting level of total factor VII after therapy was not associated with the change in the fasting level of active factor VII (r = 0.27; P = 0.21). These findings argue against the idea that elevated levels of total factor VII underlie an increased risk of arterial thromboembolism in postmenopausal women using unopposed estrogen replacement.
Compression Ultrasonography of the Leg Veins in Patients with Clinically Suspected Pulmonary Embolism
Authors: Sanson Bernd-Jan , Büller Harry , Brandjes Dees P. , Mac Gillavry Melvin ,   the ANTELOPE-Study Group
Published: March 2018

SummaryWe performed a multi-center study in consecutive patients with suspected pulmonary embolism to compare the diagnostic accuracy of a two-point compression ultrasonography (only the common femoral vein and popliteal vein) with an extensive examination of compressibility (from the common femoral vein until the trifurcation of calf veins). A total of 479 patients underwent the two-point compression ultrasonography. The prevalence of pulmonary embolism was 32%. The sensitivity and specificity of this procedure were 23% (95% CI 19-26) and 98% (95% CI 96-99), respectively. Extensive compression ultrasonography was performed in 461 (96%) of these 479 patients and showed comparable accuracy indices (sensitivity 25%, 95% CI 20-28 and specificity 97%, 95% CI 95-99). We conclude that compression ultrasonography has a limited sensitivity for the detection of thrombosis in patients with acute pulmonary embolism within 24 h of presentation. A more extensive assessment of compressibility of the leg veins in these patients has no additional value as compared to the two-point assessment.
Endogenous Clotting Factor Activity and Long-term Outcome in Patients with Moderate Haemophilia
Authors: van der Bom J. G. , Mauser-Bunschoten E. P. , Roosendaal G. , Beek F. J. A. , de Kleijn P. , Grobbee D. E. , van den Berg H. M. , Fischer K. 
Published: March 2018

SummaryIn order to address the question of the optimum target level for prophylactic treatment of severe haemophilia patients, the association between endogenous clotting factor activity and outcome was studied in a cohort of 46 patients with moderate haemophilia. Data on treatment and outcome were collected annually.Median follow-up was 8.0 years (range 1-26). Median joint bleed frequency was 1 per year and median radiological score according to Pettersson was 1 point (max. 78) at the age of 25 years. One percent increase in clotting factor level was associated with a 4 months later onset of joint bleeds (95% Confidence Interval (CI): 2-6 months) and a 16% lower Pettersson score (95% CI: 3-27%). No statistically significant effect of clotting factor activity on joint bleed frequency could be demonstrated.These findings confirm that patients with moderate haemophilia experience only mild arthropathy, and provide evidence for a protective effect of higher clotting factor levels on joint damage.