bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, Pharmacodynamics and Tolerability of a Potent, Non-peptidic, GP IIb/IIIa Receptor Antagonist following Multiple Oral Administrations of a Prodrug Form
Authors: Modi Nishit , Bullens Sherron , Pater Cheryl , Lipari Michael , Robarge Kirk , Blackburn Brent , Beresini Maureen , Weller Thomas , Steiner Beat , Bunting Stuart , Refino Canio 
Published: March 2018

SummaryRo 44-3888 is a potent and selective antagonist of GP IIb/IIIa. Following IV administration to rhesus monkeys, the (mean ± SD.) clear ance, volume of distribution and terminal half-life of Ro 44-3888 were 4.4 ± 1.8 ml/min/kg, 0.8 ± 0.4 l/kg and 2.5 ± 0.8 h respectively. Oral administration of Ro 48-3657 (1 mg/kg), a doubly protected prodrug form, produced peak concentrations of Ro 44-3888 (152 ± 51 ng/ml), 4.2 ± 2.2 h after dosing. Terminal half-life and estimated bioavailabil ity were 5.1 ± 1.6 h and 33 ± 6% respectively. No effect on blood pressure, heart rate or platelet counts were seen. Adenosine diphosohate (ADP) induced platelet aggregation (PA) and cutaneous bleeding times (CBT) were determined prior to and after the last of 8 daily oral administrations of Ro 48-3657 (0.25 or 0.5 mg/kg) to eight rhesus monkeys. Peak and trough plasma concentrations were proportional to dose and steady state was achieved after the second administration. Inhibition of PA and prolongation of CBT were concentration dependent. The ex vivo IC50 (82 nM) for ADP-mediated PA correlated with a value (58 nM) determined in vitro. The CBT response curve was displaced to the right of the PA curve. CBT was prolonged to ≥25 min when levels of Ro 44-3888 exceeded 190 nM and PA was >90% inhibited. Therefore, in rhesus monkeys, Ro 48-3657 is reproducibly absorbed and converted to its active form, is well tolerated, and has a concentration-dependent effect on PA and CBT. These properties make Ro 48-3657 an attractive candidate for evaluation in patients at high risk for arterial thrombosis.
Association of a Common Polymorphism in the Factor XIII Gene with Myocardial Infarction
Authors: Kohler Hans , Stickland Max , Ossei-Gerning Nicholas , Carter Angela , Mikkola Hanna , Grant Peter 
Published: March 2018

SummaryFactor XIII when activated by thrombin, crosslinks fibrin, however its role in thrombotic disorders is unknown. A common point mutation (G T) in exon 2 of the A-subunit gene which codes for an amino acid change three amino acids from the thrombin activation site (Factor XIIIVal34Leu) is a candidate for a role in the pathogenesis of acute myocardial infarction. Factor XIII genotype frequencies were determined in a case-control study of 398 caucasian patients and 196 healthy controls. Patients had undergone angiography for investigation of coronary artery disease and were evaluated for a history of myocardial infarction. The prevalence of the mutation was lower in patients with myocardial infarction than without (32% vs. 50%), p = 0.0009 and than in controls (32% vs. 48%), p = 0.005. Patients possessing the mutation with a history of myocardial infarction had higher PAI-1 concentrations (mean, 27.9 vs. 16.7 ng/ml, p = 0.004) and the PAI-1 4G/4G genotype was commoner (43% vs. 26%, p = 0.03). There was no difference in PAI-1 4G/4G genotype (33% vs. 32%) and PAI-1 levels (mean, 21.0 vs. 20.9 ng/ml) in patients possessing wild type with MI compared to those without MI. These results indicate that the G T mutation coding for factor XIIIVal34Leu is protective against myocardial infarction and suggest a mechanism whereby elevated levels of PAI-1 may contribute to vascular risk.
Solid Tumors and Factor VIII Antibodies
Authors: Hauser Irene , Lechner Klaus 
Published: March 2018

Summary
Purpose: To analyze the association between solid tumors and the occurrence of factor VIII antibodies and the response to treatment.
Patients and Methods: Published case reports describing the association of a solid tumor and a factor VIII antibody retrieved from 20 data bases. 40 cases were reported and 27 cases were analyzable.
Results: Factor VIII antibodies occurred in a close temporal relationship with the detection of the tumor in most cases. No association with a specific type of tumor could be identified. Immune suppressive treatment with prednisone ± cyclophosphamide was successful in the majority of cases.
Conclusion: It is likely that there is a causal association between some solid tumors and factor VIII antibodies, but it is an extremely rare complication of cancer. The immunoglobuline nature of the inhibitor and the good response to immune suppressive treatment suggests that it is an autoimmune phenomenon. The pathogenesis is unknown.
Factor XIIa Is a Kinetically Favorable Plasminogen Activator
Authors: Feddersen Karina , Røjkjær Rasmus , Schousboe Inger 
Published: March 2018

SummaryInitiation of the plasma contact system has been shown to play a significant role in the fibrinolysis, activating both pro-urokinase and plasminogen. The aim of the present study was to further evaluate the functional role of the factor XIIa catalyzed activation of plasminogen. Activation of plasminogen by factor XIIa followed the Michaelis-Menten rate equation. In a continuous assay system the Km was 0.27 μΜ; the kcat 0.078 min−1 and the kcat/Km 0.31 × 106 Μ−1 × min−1. In an endpoint assay system the Km was 0.58 μΜ; the kcat 0.096 min−1 and the kcat/Km 0.16 × 106 Μ−1 × min−1. The discrepancy between the kcat in the two assays is not significant. Theoretically the higher Km in the end-point assay system may be due to the presence or generation of an unidentified competitive inhibitor in this assay system. Comparing the catalytic constants of factor XIIa with those of urokinase activation of plasminogen, the specificity constant, kcat/Km, of factor XIIa activation of plasminogen was 20-fold lower. However, taking the low physiological concentration of urokinase into account, the efficiency of activated factor XII is equivalent to that of urokinase. When monitoring factor XIIa activation of plasminogen in a clot lysis assay, the clot lysis time was 2- to 4-fold as long as that accommodated by urokinase at factor XIIa concentrations equivalent with 5-20% of the zymogen concentration in plasma. The factor XIIa mediated clot lysis was prevented completely by the presence of a polyclonal antibody to factor XII.
Longevity Is Independent of Common Variations in Genes Associated with Cardiovascular Risk
Authors: Andersen-Ranberg Karen , de Maat Moniek , Kristensen Søren Risom , Jeune Bernard , Gram Jørgen , Jespersen Jørgen , Bladbjerg Else 
Published: March 2018

SummaryDo extremely old persons have a genetically favourable profile which has protected them from cardiovascular death? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [factor VII, FVII (R/Q353, intron 7 (37bp)n, and -323ins10), β fibrinogen (-455G/A), plasminogen activator inhibitor type 1, PAI-1 (-675(4G/5G)), tissue plasminogen activator, t-PA (intron 8 ins311), platelet receptor glycoprotein IIb/IIIa, GPIIb/IIIa (L/P33), prothrombin (20210G/A), methylene tetrahydrofolate reductase, MTHFR (A/V114), angiotensin converting enzyme, ACE (intron 16 ins287), and angiotensinogen (M/T235)]. Blood was collected from 187 unselected Danish centenarians, and 201 healthy Danish blood donors, aged 20-64 years (mean age 42 years). Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele-specific amplification followed by agarose gel electrophoresis. The frequencies of the high-risk alleles in centenarians were: for FVII R/Q353 0.91; for FVII intron 7 (37bp)n 0.67; for FVII-323 ins10 0.90; for fibrinogen 0.16; for PAI-1 0.52; for t-PA 0.59; for GPllb/llla 0.16; for prothrombin 0.008; for MTHFR 0.33; for ACE 0.52; and for angiotensinogen 0.36. Comparable frequencies were observed in the blood donors. Subgroup analysis of men and women separately gave similar results. The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms, and this study suggests that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity.
Collagen or Collagen-related Peptide Cause [Ca2+]i Elevation and Increased Tyrosine Phosphorylation in Human Megakaryocytes
Authors: Melford S. K. , Bunce C. M. , Gibbins J. , Watson S. P. , Mountford J. C. 
Published: March 2018

SummarySince megakaryocytes are the cellular precursors of platelets we have investigated whether they share responses to platelet agonists, in particular collagen. Although previous studies have reported responses to thrombin in non-human megakaryocytes, through studies of single cell calcium responses and protein tyrosine-phosphorylation we demonstrate for the first time that both isolated human megakaryocytes and CD41/61-positive megakaryocytes derived in culture from CD34+ cells share responses to the platelet agonists collagen, collagen-related peptide and thrombin. The responses to either collagen or CRP were seen only in the most mature megakaryocytes and not in mega-karyocyte-like cell lines, suggesting that the response to collagen is a characteristic developed late during megakaryocyte differentiation. These primary cells offer the opportunity to use many molecular and cellular techniques to study and manipulate signalling events in response to platelet receptor agonists, which cannot be performed in the small, anucleate platelet itself.
The Factor V Gene A4070G Mutation and the Risk of Venous Thrombosis
Authors: Nicaud Viviane , Gandrille Sophie , van Dreden Patrick , Amiral Jean , Aubry Marie-Laurence , Fiessinger Jean-Noël , Emmerich Joseph , Aiach Martine , Alhenc-Gelas Martine 
Published: March 2018

SummaryThe A4070G polymorphism in exon 13 of the factor V (FV) gene, which replaces His by Arg at position 1299 of the B domain, was recently shown to influence circulating FV levels and to contribute to the activated protein C (APC) resistance phenotype. We examined the impact of this polymorphism in a population of unselected patients with venous thromboembolic disease (VTE). The prevalence of the G4070 (R2) allele was determined in 205 patients and 394 healthy subjects of similar age and sex distribution. Thirty-seven patients (18%) were heterozygous for the R2 allele and 1 (0.5%) was homozygous. Forty-four controls (11.2%) were heterozygous for the R2 allele and 1 (0.2%) was homozygous. Thus, the allelic frequency was significantly higher in the patients with VTE than in the healthy controls, with respective values of 9.5% and 5.8%. The odds ratio was 1.8 (95% CI: 1.1-2.8, p = 0.02), pointing to an increased risk of VTE in carriers of the R2 allele. After excluding subjects with putative or confirmed gene defects (mainly the FV R506Q mutation), the R2 allele was still a risk factor for VTE in the remaining patients, with an odds ratio of 2.0 (95% CI: 1.2-3.5, p = 0.01), demonstrating that this polymorphism is itself a risk factor. This study also confirms that the R2 allele influences APC resistance (APCR) in the absence of the FV R506Q mutation.
Low Levels of Heparin-releasable Tissue Factor Pathway Inhibitor in Young Patients with Thrombosis
Authors: Alberio G. , Moia M. , Mannucci P. M. , Ariëns R. A. S. 
Published: March 2018

SummaryAn association between deficiency of tissue factor pathway inhibitor (TFPI) and thrombosis has not been clearly demonstrated in humans, but previous studies have focused on the measurement of plasma TFPI, which is only a small part of the total body TFPI. The major fraction of this natural anticoagulant can be measured in plasma after release by heparin injection. To investigate if deficiency of heparin-releasable TFPI is associated with thrombosis, we measured TFPI activity in plasma before and 10 min after intravenous injection of 7500 IU unfractionated heparin in 64 young patients with venous thrombosis, 49 young patients with arterial thrombosis and 38 healthy individuals. Post-heparin TFPI activity levels were significantly lower in the group of patients with venous thrombosis than in controls (mean ± SD: 230% ± 39 vs 260% ± 34, p = 0.0002), whereas there was no difference for patients with arterial thrombosis. Defining the normal range as the mean ± 2 SD of TFPI activity in controls, twelve patients had low post-heparin TFPI activity levels, seven with venous and five with arterial thrombosis. Low levels of TFPI activity were confirmed by immunoassay in six of the seven patients with venous thrombosis and two of the five patients with arterial thrombosis, and were present also in at least one first degree relative of six patients, suggesting that the defect might be inheritable. However, the causative role of low heparin-releasable TFPI remains uncertain, because co-segregation of the defect with thrombotic symptoms could not be demonstrated in the small number of families studied.
Post-DDAVP Thrombocytopenia in Type 2B von Willebrand Disease Is not Associated with Platelet Consumption: Failure to Demonstrate Glycocalicin Increase or Platelet Activation
Authors: Steffan A. , Pontara E. , Zucchetto A. , Rossi C. , De Marco L. , Girolami A. , Casonato A. 
Published: March 2018

SummaryThrombocytopenia is frequently reported in type 2B von Willebrand disease (vWD), and thought to be related to the abnormally high affinity of 2B von Willebrand factor (vWF) for platelet GPIb-IX. To gain an insight into the nature of this thrombocytopenia, we measured plasma glycocalicin (GC) levels (as a marker of platelet turnover), and platelet surface expression of the alpha granule protein P-selectin (as a marker of platelet activation) in 9 patients with type 2B vWD before, and in 4 patients also following the infusion of 1-desamino-8-d-arginine vasopressin (DDAVP). Three patients presented a persistent decrease of platelet counts in the resting condition. GC levels were within the normal range, regardless of the platelet counts, in all but one patient who presented, on the other hand, a normal platelet count. Moreover, platelets expressed normal amounts of P-selectin on their surface, regardless of platelet counts. These findings suggest that the thrombocytopenia observed in type 2B vWD is not due to platelet activation and subsequent consumption in circulation.Despite a significant, albeit transient, decrease in platelet count, DDAVP did not induce an increase in plasma GC levels, nor enhance P-selectin expression. These observations indicate that the acute post-DDAVP thrombocytopenia in type 2B vWD is not related to platelet activation and consumption. We advance that the post-DDAVP 2B vWF is hemostatically more active, and able to induce agglutination but not aggregation of circulating platelets. This would explain both the prompt recovery of basal platelet counts after the post-DDAVP decrease, and the lack of reported thrombotic complications in this disorder.Therefore, even though 2B vWF is characterized by an enhanced affinity for the platelet surface, its binding to platelet GPIb-IX in the soluble phase is not able to induce true platelet aggregation; vWF thus appears to be mainly an adhesive protein, rather than an aggregating agent.
Comparison of the Effects of Apo(a) Kringle IV-10 and Plasminogen Kringles on the Interactions of Lipoprotein(a) with Regulatory Molecules
Authors: Green Michael , LoGrasso Philip , Boettcher Brian , Madison Edwin , Curtiss Linda , Miles Lindsey , Xue Song 
Published: March 2018

SummaryLipoprotein(a) [Lp(a)] is associated with atherosclerosis and with disease processes involving thrombosis. Lp(a) contains apoprotein (a) [apo(a)], which has a sequence highly homologous to plasminogen. Hence, Lp(a) binds directly to extracellular matrix, cellular plasminogen receptors and fibrin(ogen) and competes for the binding of plasminogen to these regulatory surfaces. These interactions may contribute to the proatherothrombogenic consequences of high Lp(a) levels. These interactions are mediated by lysine binding sites (LBS). Therefore, we examined the role of apo(a) kringle IV-10 [the only apo(a) kringle demonstrated to exhibit lysine binding activity in the intact lipoprotein] in the interaction of Lp(a) with these regulatory molecules. We have compared directly apo(a) KIV-10 with plasminogen K4 to examine whether these highly structurally homologous kringle modules are also functionally homologous. Futhermore, because the plasminogen K5-protease domain (K5-PD) binds directly to fibrin, we have also examined the ability of this plasminogen fragment to inhibit the interaction of Lp(a) with these regulatory molecules and with extracellular matrix. Apo(a) KIV-10 competed effectively for the binding of 125I-Lp(a) to these surfaces but was less effective than either intact Lp(a), plasminogen K4 or plasminogen. Plasminogen K5-PD was a better competitor than apo(a) KIV-10 for 125I-Lp(a) binding to the representative extra-cellular matrix, Matrigel, and to plasmin-treated fibrinogen. In contrast, plasminogen K5-PD did not compete for the interaction of Lp(a) with cells, although it effectively competed for plasminogen binding. These results suggest that Lp(a) recognizes sites in all of the regulatory molecules that are also recognized by apo(a) KIV-10 and that Lp(a) recognizes sites in extracellular matrix and in plasmin-modified fibrinogen that also are recognized by plasminogen K5-PD. Thus, the interaction of Lp(a) with cells is clearly distinct from that with extracellular matrix and with plasmin-treated fibrinogen and the recognition sites within Lp(a) and plasminogen for these regulatory molecules are not identical.Portions of this manuscript were presented at the 69th Meeting of the American Heart Association, New Orleans, LA 1996.
Induction of Hypercoagulability Condition by Chronic Localized Cold Stress in Rabbits
Authors: Khatun Selina , Belayet Hossain , Tokunaga Naoki , Sumimoto Kazuhiro , Kobayashi Takao , Terao Toshihiko , Kanayama Naohiro 
Published: March 2018

SummaryTo evaluate the effect of cold-induced stress on renal and hepatic blood flow and coagulation parameters, rabbits’ soles were exposed to ice pad (0° C). Renal and hepatic blood flow was measured after 1 h and 15 days of cold stress. Coagulation parameters (0, 8th and 15th days of stress) and histological studies were performed. Renal and hepatic blood flow was significantly reduced after cold-stress. Decreased platelet count, antithrombin III (AT III) activity, increased fibrinogen (Fbg) level, shortened activated partial thromboplastin time (aPTT) and prothrombin time (PT) was found after 8 and 15 days of cold-stress. Histology showed enlarged glomeruli with fibrin deposition in kidney, ischemic changes and fibrin deposition in liver and hemorrhagic necrosis in adrenal cortex. We conclude that undesirable localized cold induced sympathetic stimulation in daily life may be a predisposing factor for coagulopathy.
Enhancement of Protein S Anticoagulant Function by β2-glycoprotein I, a Major Target Antigen of Antiphospholipid Antibodies:
Authors: Wei Zhang Hong , Shen Christine , Butman Bryan , Jeffries Eddie , Lahita Robert , Myones Barry , Merrill Joan 
Published: March 2018

SummaryThrombosis in the antiphospholipid syndrome has been associated with acquired deficiency of the anticoagulant protein S. We sought evidence that β2-glycoprotein I, a major target antigen for antiphospholipid antibodies, is involved in regulation of protein S activity. Incubation of purified protein S or plasma with β2-glycoprotein I reversed functional modulation of protein S by its plasma inhibitor, the C4b-binding protein. In a plasma-free ELISA, β2-glycoprotein I prevented the binding of protein S and C4b-binding protein when pre-incubated with immobilized protein S but not when similarly preincu-bated with C4b-binding protein. β2-glycoprotein I in fluid phase interfered with precipitation of protein S by sepharose-bound C4b-binding protein. Effects of β2-glycoprotein I on protein S function were inhibited by one of four monoclonal anti-β2-glycoprotein I antibodies. These data suggest that β2-glycoprotein I helps maintain adequate plasma levels of circulating free, active protein S. Antiphospholipid (anti-β2-glycoprotein I) antibodies might cause sporadic thrombosis, at least in part, by impairing this novel regulatory mechanism.
The Sensitivity and Specificity of Commercial Reagents for the Detection of Lupus Anticoagulant Show Marked Differences in Performance between Photo-optical and Mechanical Coagulometers
Authors: Mackie I. J. , Purdy G. , Machin S. J. , Lawrie A. S. 
Published: March 2018

SummaryThis study was undertaken to appraise the application of those reagents most widely used in the UK for the detection and confirmation of lupus anticoagulant (LA) on an Amelung KC4A and a Sysmex CA-6000™ coagulometer. Five sets of dilute Russell’s viper venom time (DRVVT) reagents were assessed as well as the Textarin®-PL/ Ecarin ratio. Each DRVVT method comprised both LA detection and confirmation reagents provided by the same manufacturer. Samples were obtained from 20 normal healthy subjects, 10 LA-positive patients, 10 patients receiving oral anticoagulant therapy (OAT) who had previously been documented as LA-positive, a further 10 LA-negative patients receiving OAT and 10 LA-negative patients receiving unfractionated heparin therapy.
The sensitivity and specificity of the reagents exhibited considerable variation not only between reagents, but also when the same reagent was used on the two analysers. Sensitivity ranged from 62 to 97% (all reagents both analysers), specificity went as low as 23% (Gradipore reagent on the CA-6000™) and as high as 100% (American Diagnostica Inc on both KC4A and CA-6000™). On the KC4A instrument, Unicorn Diagnostics’ lupus anticoagulant kit offered the best compromise of sensitivity and specificity (sensitivity 83% and specificity 81%). On the CA-6000™ the reagents supplied by American Diagnostica Inc exhibited optimal performance (sensitivity 90% and specificity 100%). The results indicate a need to optimise test reagents for specific analyser types, a procedure which can only be undertaken with preparations such as the proposed NIBSC reference plasmas for the detection of lupus anticoagulant.
Transcriptional Regulation of the Murine Urokinase-type Plasminogen Activator Gene in Skeletal Myoblasts
Authors: Miralles Francesc , Ibáñez-Tallon Inés , Parra Maribel , Crippa Massimo , Blasi Francesco , Besser Daniel , Nagamine Yoshikuni , Muñoz-Cánoves Pura 
Published: March 2018

SummaryWe have previously shown that urokinase-type plasminogen activator (uPA) is highly expressed in murine C2C12 myoblasts and that antibodies against uPA are able to block both myoblast fusion and differentiation. Here we show the characterization of cis-acting elements in the mouse uPA promoter in vitro which are involved in uPA gene expression in C2C12 myoblast cells. DNase I hypersensitive (HS) site analysis revealed the presence of three HS sites in myoblasts. Deletion analysis of stably transfected uPA-promoter constructs revealed that at least two of the three HS sites accounted for the high transcriptional expression in C2C12 cells. One was located at -2.4 kb and corresponded to a known PEA3/AP1A element and the other one was located at -4.9 kb and contained a CArG box and a CRE element. So far, no regulatory function had been assigned to this CRE/CArG element. Both HS sites alone were able to activate transcription of a heterologous promoter and showed a cooperative effect when placed together. Electrophoretic mobility-shift assays using myoblast nuclear extracts and specific antibodies demonstrated that cJun, JunD and ATF2 bound to the PEA3/AP1A element, whereas the CRE/CArG element bound SRF. Altogether, these results suggest that high uPA expression in myoblasts is dependent on the cooperation of two regulatory sites in the uPA promoter.