bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coagulation Markers Predict Survival in Cancer Patients
Authors: Haeberli A. , Vogt A. , Woodtli K. , Henkel E. , Furrer Th. , Fey M. F. , Beer J. H. 
Published: March 2018

SummaryIn order to prospectively evaluate the predictive value of coagulation markers such as the fibrin Ddimer for survival of cancer patients, we analyzed their role in a prospective study at a University Hospital Institute of Medical Oncology.268 consecutive outpatients with cancer were included, 72 in remission and 196 with active disease. All cause mortality in relation to the marker levels was measured.99/268 patients died during the observation period of 4484 patient months (mean: 17 months). Patients with active disease had a significant, 1.5-5-fold increased marker concentration compared to patients in remission. When analyzed in quartiles, the data showed a lower than predicted death rate in the first quartile and a significantly elevated mortality in the fourth marker quartile. The odds ratio for death predicted by the fibrin monomer (FM) in the fourth vs. the first quartile was 4.1 (95% C. I.: 1.7-9.7) and p = 0.005 for the multivariate analysis of the markers.We conclude that a single determination of coagulation markers, particularly of TAT, FM, and Ddimer is sufficient to strongly predict survival in cancer patients over the following 1-3 years.
The Role of the Factor X Activation Peptide: A Deletion Mutagenesis Approach
Authors: Mullane Michael , Porche-Sorbet Rhonda , Daust Heather , Miletich Joseph , Rudolph Amy 
Published: March 2018

SummaryTo understand the role of the factor X (fX) activation peptide (AP), a deletion mutagenesis approach was employed. Two single-chain, variant enzymes were generated in which 41 residues were deleted from the AP: fXdes-137-183 and fXdes-137-183;N191A, which lacks a carbohydrate moiety at Asn191 due to an alanine substitution. Deletion of the fX AP did not impact fXa catalytic activity. Activation of the variant zymogens, however, was altered. Neither mutant enzyme was activated by the fX coagulant protein from Russell’s viper venom (RVV-X1). Activation by factor VIIa (fVIIa) and fVIIa in the presence of cofactor, lipidated tissue factor (TF), occurred at an accelerated rate for both variants as compared to wild-type fX (WTfX). Similar to fVII, the mutants auto-activated in a cofactor-independent manner, which was characterized by a lag period and accelerated dose-dependently by plasma fXa (kcat/Km, 0.046 ± 0.004 µM−1s−1). Both mutants were also found to be activated by fVIIa (0.31 ± 0.03 µM−1s−1), fIXa (0.30 ± 0.03 µM−1 s−1), and thrombin (0.00078 ± 0.00015 µM−1s−1). In all cases, the rate of activation was faster for fXdes-137-183;N191A as compared to fXdes-137-183. We propose that the fX AP and Asn191 carbohydrate serve primarily as negative autoregulation mechanisms to prevent spurious activation of fX and secondarily in cofactor dependence and activator specificity.The abbreviations used are: TF, human tissue factor; AP, activation peptide; HEPES, (N-[2-Hydroxyethyl]piperazine-N’-[2-ethanesulfonic acid]); PEG, polyethylene glycol 8000; BSA, bovine serum albumin; Tris, (Tris[hydroxymethyl] aminomethane); EDTA, (Ethylenedinitrilo)-tetraacetic acid; SDSPAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; RVV-X, X activating protein from Russell’s viper venom; gla, γ-carboxylated glutamic acid; WTfX, wild type factor X; PC:PS, phosphatidylcholine:phosphatidylserine; fXa, fIXa, f Va, fVIIa, and fVIIIa, activated coagulation factor X, IX, V, VII, and VIII; ATIII, antithrombin; TFPI, tissue factor pathway inhibitor.
Diurnal Variation in PAI-1 Activity Predominantly Confined to the 4G-allele of the PAI-1 Gene
Authors: Hoekstra Tiny , Schouten Evert , Kluft Cornelis , Geleijnse Johanna 
Published: March 2018

SummaryWe examined the diurnal pattern in Plasminogen Activator Inhibitor-type 1 (PAI-1) activity and Plasminogen activator (t-PA) in relation to the 4G/5G-polymorphism in the promoter of the PAI-1 gene. The analyses were performed in the Arnhem Elderly Study, a populationbased study of 598 elderly. A single blood sample was drawn and the time of blood sampling was recorded (between 8 a. m. and 5.30 p. m.). Plasma PAI-1 activity was strongly associated with time of blood sampling, showing the highest values in the early morning. The diurnal pattern was clearly present in the 4G/4G (n = 184) and 4G/5G (n = 275) genotypes, but not in the 5G/5G-genotype (n = 139). T-PA antigen showed a weak diurnal variation, which did not differ across the variants of the 4G/5G-polymorphism. Our findings raise the hypothesis that 5G-homozygotic persons may be relatively protected from diurnal variation in the occurrence of coronary events.
Trophic Effects of Platelets on Cultured Endothelial Cells are Mediated by Platelet-associated Fibroblast Growth Factor-2 (FGF-2) and Vascular Endothelial Growth Factor (VEGF)
Authors: Pintucci Giuseppe , Froum Scott , Pinnell Jared , Mignatti Paolo , Rafii Shahin , Green David 
Published: March 2018

SummaryIn addition to their role in primary hemostasis, platelets serve to support and maintain the vascular endothelium. Platelets contain numerous growth factors including the potent angiogenic inducers VEGF and FGF-2. To characterize the function of these two plateletassociated growth factors, the effects of the addition of purified platelets to cultured endothelial cells were examined. The survival and proliferation of endothelial cells were markedly stimulated (2-3-fold and 5-15-fold respectively) by the addition of gel-filtered platelets. Acetylsalicylic acid-treated or lyophilized fixed-platelets were ineffective in supporting endothelial cell proliferation. In Transwell assays, the stimulatory effect of platelets on endothelial cells was preserved, consistent with an effect mediated by secreted factors. The combined inhibition of VEGF and FGF-2 by neutralizing antibodies, in contrast to inhibition of either alone, abrogated both platelet-induced endothelial cell survival and proliferation. FGF-2 isoforms were detected in platelet lysates, as well as in the releasates of agonist-stimulated platelets. Megakaryocytes generated by ex vivo expansion of hematopoietic progenitor cells with kit ligand and thrombopoietin were analyzed for expression of FGF-2. Punctate cytoplasmic staining but no nuclear staining was observed by immunocytochemistry consistent with possible localization of the growth factor to cytoplasmic granules. The addition of platelets to cultured endothelial cells activated extracellular signal-regulated kinase (ERK) in a dose and time-dependent manner. This effect was abrogated by both anti-FGF-2 and anti-VEGF antibody. Since FGF-2 and VEGF are potent angiogenic factors and known endothelial cell survival factors, their release by platelets provides a plausible mechanism for the platelet support of vascular endothelium.
Acute Thrombocytopenia in Patients Treated with the Oral Glycoprotein IIb/IIIa Inhibitors Xemilofiban and Orbofiban: Evidence for an Immune Etiology
Authors: Brassard Jacqueline , Curtis Brian , Cooper Richard , Ferguson John , Komocsar Wendy , Ehardt Maria , Kupfer Stuart , Maurath Clement , Swabb Edward , Cannon Christopher , Aster Richard 
Published: March 2018

SummaryThrombocytopenic episodes occurring in 18,845 patients treated with the GPIIb/IIIa inhibitors xemilofiban and orbofiban (“fibans”) were analyzed by a blinded review panel and 73 patients were classified as having “possible fiban-induced thrombocytopenia”. When the treatment codes were broken, a significant association between drug exposure and assignment to this group was found (p <0.001). Twenty-eight (82%) of 34 archived serum samples from these patients contained fiban-dependent antibodies specific for GPIIb/IIIa, but no such antibodies were found in 61 drug treated patients not classified as having “possible fiban-induced thrombocytopenia” (p <0.001). We conclude that fiban-dependent antibodies were the major cause of acute, severe thrombocytopenia in patients judged on the basis of clinical findings to have thrombocytopenia “possibly-induced” by xemilofiban and orbofiban. Measurement of drug-dependent antibodies may be helpful in determining the basis for acute thrombocytopenia in fiban-treated patients and possibly for identification of patients at risk to develop thrombocytopenia.
Pretreatment with Oral Anticoagulants Decreases Platelet Activation in Patients Before and After Percutaneous Coronary Intervention
Authors: Gerritsen Wim , Haas Fred , Kelder Johannes , Verheugt Freek , Plokker H. W. , Berg Jurriën M. 
Published: March 2018

SummaryPlatelet activation plays a major role in acute vessel closure after coronary angioplasty. In the randomized Balloon Angioplasty and Anticoagulation Study (BAAS), pretreatment with oral anticoagulants in addition to aspirin resulted in a 47% reduction of acute complications as compared with aspirin alone. This result may suggest a direct effect of oral anticoagulants on platelet activation.Patients were randomized to aspirin alone (group A, n = 26) or to aspirin plus oral anticoagulants started one week before angioplasty (group B, n = 26). Platelet response tests were performed 1 hour before (baseline) and 1 hour after intervention and on day 1. Platelet activation was measured by flow cytometry, as the number of antibody-positive platelets per 10,000 counted. Platelet function was evaluated with use of the PFA-100® analyzer. In group B, the median number of P-selectin-positive platelets was lower before (28 vs. 54, P = 0.018) and after (13 vs. 24, P = 0.377) angioplasty than in group A. Also the median decrease in the number of P-selectin-positive platelets during angioplasty was lower in group B (Δ = 4) than in group A (Δ = 30, P = 0.022). No further significant change was observed in platelet activation on day 1 in the two groups. The ability of platelets to become stimulated as measured with the PFA-100® analyzer was not affected by oral anticoagulants.Pretreatment with oral anticoagulants resulted in less activated platelets before and after coronary angioplasty, which is in agreement with its clinical effect of reducing procedural complications. Platelet function was not affected by oral anticoagulants.
Coagulation Factor VII Activity, Arg/Gln353 Polymorphism and Features of Insulin Resistance in First-Degree-Relatives of South Asian Patients with Stroke
Authors: Catto Andrew , Young John , Bamford John , Bavington John , Grant Peter , Kain Kirti 
Published: March 2018

SummaryThe aim of the study was to determine associations of factor VII:C levels in 140 South Asian stroke subjects and 143 first-degree relatives versus age-sex matched 146 control subjects without a personal or a family history of stroke subjects living in UK. There were no significant differences in Factor VII:C levels or FVII Msp I gene polymorphism (Arg-Gln 353) R353Q genotype frequency between the groups. R353Q genotype determined Factor VII:C levels in all the three groups. Factor VII:C levels correlated with triglycerides (patients, r = 0.23; relatives r = 27; control subjects, r = 0.24) and plasminogen activator inhibitor activity (patients, r = 0.30; relatives r = 0.22; control subjects r = 0.20) in all the three groups, but with insulin only in patients (p = 0.19). Circulating levels of Factor VII:C are determined by R353Q genotype and cluster with other risk factors associated with insulin resistance in South Asian ischaemic stroke patients, first-degree relatives and control subjects but are not related to stroke or a family history of stroke.
Targeted Inactivation of the Mouse Locus Encoding Coagulation Factor XIII-A: Hemostatic Abnormalities in Mutant Mice and Characterization of the Coagulation Deficit
Authors: Lauer Peter , Metzner Hubert , Zettlmeißl Gerd , Li Meng , Smith Austin , Lathe Richard , Dickneite Gerhard 
Published: March 2018

SummaryBlood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. Plasma fibrin γ-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII. Homozygous mutant mice were fertile, although reproduction was impaired. Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival. Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin® P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.
Localization and Identification of Thrombin and Plasminogen Activator Activities in Model Human Thrombi by in situ Zymography
Authors: Robbie Linda , Berry Susan , Bennett Bruce , Mutch Nicola , Moir Elaine , Booth Nuala 
Published: March 2018

SummaryHuman thrombi vary in their susceptibility to lysis and this is clinically important. Several potential contributory factors were examined in this study by using model thrombi, created under flow; these provide a robust, reproducible and easily-manipulated system. Here we identify the plasminogen activators (PA) active in model thrombi of known age and define the cellular and plasma contribution to activity in different areas. The cell-rich head of model thrombi had strong thrombin and PA activity, with coagulant activity also at the tail. Thrombin activity decreased as model thrombi were aged. PA activity in the thrombus head also decreased on ageing of thrombi but activity emerged around the thrombi, including the tail. Activity in the head of fresh model thrombi was primarily due to uPA, with some contribution from tPA. Experiments with thrombi prepared from platelet-rich plasma and added leucocytes showed that uPA activity at the head of fresh thrombi was derived from PMN. Older thrombi had tPA activity around the tail of the thrombus; this activity occurred in the absence of cells. This study highlights the importance of PMN-derived uPA activity in the lysis of fresh thrombi, with activity originating in the leucocyte-rich head. It also shows that thrombi are dynamic structures in which fibrin can be repeatedly laid down and lysed, observations that are relevant to therapeutic lysis and potential rethrombosis.
Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Levels in Patients with Coronary Artery Disease Investigated by Angiography
Authors: Schroeder Verena , Chatterjeel Tushar , Mehta Haresh , Windecker Stephan , Pham Trinh , Devantay Nicolas , Meier Bernhard , Kohler Hans 
Published: March 2018

SummaryDue to its role in the balance between coagulation and fibrinolysis, thrombin activatable fibrinolysis inhibitor (TAFI) may be involved in the development of cardiovascular diseases. We studied 362 patients with coronary artery disease (CAD) and 134 control subjects free of CAD, both groups investigated by angiography. TAFI antigen levels were determined in venous and intracoronary plasma samples and were related to metabolic and hemostatic risk factors and extent of coronary atherosclerosis. Venous TAFI levels tended to be higher in CAD patients compared to controls, whereas this difference was significant in intracoronary samples. A subgroup of patients who had not experienced acute myocardial infarction or undergone previous cardiac interventions showed significantly higher TAFI levels in both venous and intracoronary plasma samples. TAFI levels correlated with acute phase reactants indicating a role for TAFI in inflammation. However, TAFI levels did not correlate with extent of coronary atherosclerosis and among the classical cardiovascular risk factors TAFI levels only correlated with total cholesterol and fibrinogen concentration. Our results suggest that TAFI might be a risk factor for the development of CAD.
Flow Conditions Modulate Homocysteine Induced Changes in the Expression of Endothelial Cell Genes Associated with Cell-Cell Interaction and Cytoskeletal Rearrangement
Authors: Savion Naphtali , Gal Nurit , Varon David , Dardik Rima 
Published: March 2018

SummaryIn the present study we analyzed changes in the pattern of gene expression in endothelial cells (HUVEC) exposed to elevated homocysteine levels under flow conditions. RNA samples of untreated and homocysteine treated EC were analyzed using a human cDNA array containing 588 cDNAs relevant to the cardiovascular system. Exposure to homocysteine under flow resulted in altered expression of 8 genes, the alterations of 3 of which were further confirmed by RT-PCR analysis: upregulation of MCP-1 and of profilin-I, and downregulation of alpha-catenin. The increased expression of profilin-I and the decreased expression of alpha-catenin were also confirmed at the protein level by Western blot analysis. Furthermore, immunostaining for alpha-catenin demonstrated complete loss of the protein from intercellular junctions following exposure to homocysteine under flow. All these changes were not observed in cells exposed to homocysteine under static conditions. We show that under flow conditions, homocysteine modulates the expression of genes/proteins involved in actin cytoskeleton reorganization, as well as in the formation and/or maintenance of cellcell junction, thus contributing to the morphological changes (e.g. cell retraction) reflecting endothelial cell injury.
A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs
Authors: Mallard Luc , Elias Marie , Alquier Catherine , Guidolin François , Gauthier Bruno , Viard Alain , Mahouin Pierre , Vinel Anne , Boccalon Henri , Elias Antoine 
Published: March 2018

SummaryIn patients clinically suspected of deep-vein thrombosis (DVT) of the lower limbs, it is safe to withhold anticoagulant therapy after a negative ultrasound (US) limited to the popliteal and the femoral veins, provided that this can either be repeated or combined with other diagnostic procedures. To assess the safety of withholding anticoagulants after a single negative complete US, we performed a multicenter, prospective, cohort study including consecutive ambulatory outpatients from institutional and private practice settings, with a clinically suspected first episode of DVT. Patients fulfilling the inclusion criteria were enrolled after careful clinical assessment. A complete US examination of the proximal and the distal veins was performed according to a standardized and detailed protocol. Anticoagulant therapy was administered in patients with proximal or isolated distal DVT and withheld in those with negative results. The main outcome measure was the occurrence of objectively documented clinical thromboembolic events during a three-month follow-up after a negative US.Out of 623 patients,401 (64.4%) had a baseline negative US, were not anticoagulated and could be followed-up for three months. Two patients presented a calf DVT within three months. The incidence of venous thromboembolic events, including distal DVT, was 0.5% [95% confidence interval: 0.1-1.8]. No proximal DVT, or non-fatal or fatal pulmonary embolism occurred (incidence: 0.0% [95% confidence interval: 0.0-0.9]).In conclusion, it is safe to withhold anticoagulant therapy in patients with clinically suspected DVT after a single, negative, complete US. Integrating this method within diagnostic strategies for DVT could improve management and be more acceptable for patients and physicians.
Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis
Authors: Schwarz Thomas , Halbritter Kai , Beyer Jan , Siegert Gabriele , Oettler Wolfram , Schmidt Benjamin , Schroeder Hans , Schellong Sebastian 
Published: March 2018

SummaryNoninvasive diagnosis of deep vein thrombosis (DVT) is based on ultrasound examination of the leg veins, usually restricted to only compression of the proximal veins (CUS). Patients with negative CUS findings require a second examination or a combination with other tests, which impairs clinical efficiency. In this prospective outcome study, 1646 consecutive patients with clinically suspected DVT were examined once by a standardized protocol of complete compression ultrasound comprising all proximal and distal veins (CCUS) as the only diagnostic test. The examination was equivocal in 15 patients (1% technical failure rate). Another 366 patients (22%) were tested positive for proximal DVT, distal DVT, muscle vein thrombosis, or phlebitis. Of 1265 patients in whom CCUS findings were negative, 242 met exclusion criteria for follow-up (age <18, life expectancy <3 months, other reasons for anticoagulation, postthrombotic lesions of the leg veins, or lack of informed consent). During the 3 months of follow-up, three of 1023 patients with negative CCUS findings experienced a symptomatic venous thromboembolic event (0.3% [95% CI 0.1%-0.8%]). We conclude that the CCUS protocol has a low technical failure rate and is safe with respect to excluding DVT, thereby reducing the diagnostic workup of patients with suspected DVT to a single ultrasound examination.
Impaired prothrombinase activity of factor X Gly381Asp results in severe familial CRM+ FX deficiency
Authors: Pinotti Mirko , Camire Rodney , Baroni Marcello , Rajab Anna , Marchetti Giovanna , Bernardi Francesco 
Published: March 2018

SummaryWe investigated three members of a large Omani family affected by severe factor X (FX) deficiency (coagulant activity <1%) and showing marked differences in the onset of severe hemorrhagic symptoms. All patients were homozygous for a novel FX mutation (Gly381Asp) in the structurally conserved region of the serine protease active site. Expression levels of recombinant 381D-FX were similar to those of wt-FX, indicating the presence of a severe CRM+ FX deficiency, a poorly investigated condition. The 381D-FX was normally activated and did not show a detectable amidolytic activity. Instead, we observed a residual activity in a prothrombin-time based assay (1%) and in prothrombinase assays both in plasma (1%) and in purified systems (3%). Comparison with FX variants characterized by reduced activation suggests that mutations affecting FX activity might result in a more pronounced impairment of coagulation and thus in severe hemorrhagic phenotype. In addition, this study indicates that the hemorrhagic heterogeneity observed in FX deficiencies is only partially explained by molecular analysis of FX gene.