bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tissue Thromboplastin Inhibition Test in the Detection of Lupus Anticoagulants: Importance of a Correction Factor Eliminating the Influence of Fibrinogen Level
Authors: Eschwège Valérie , Seddiki Sakina , Robert Annie 
Published: July 2018

SummaryTissue thromboplastin inhibition test (TTI) is a highly sensitive but poorly specific test used in the diagnosis of lupus anticoagulant (LA) which is usually requested for patient with inflammatory status. Therefore, we investigated the influence of fibrinogen level on TTI using Recombiplastin (Ortho), Neoplastine (Diagnostica Stago) and Throm-borel S (Behring), in a group of 84 patients with fibrinogen levels ranging from 1.6 to 11.8 g/1. The highly significant (p<0.0001) positive correlation observed between fibrinogen level and TTI with the 3 thromboplastins allowed the calculation of a new TTI value corrected for fibrinogen level named TTIfg. TTIfg was defined as TTI - (“S” × fibrinogen level) where “S” was the slope of the regression line defining TTI as a function of fibrinogen values. In the group studied, the low TTI specificity, respectively 64%, 67% and 75% with Recombiplastin, Neoplastine and Thromborel S, was greatly improved to respectively 95%, 93% and 95% when results were expressed as TTIfg. TTIfg remained as sensitive as TTI when evaluated in a group of 38 patients with previously diagnosed LA.
NMDA Receptors Play an Anti-aggregating Role in Human Platelets
Authors: Franconi Flavia , Miceli Mauro , Graziella De Montis Maria , Crisafi Elena Lupis , Bennardini Federico , Tagliamonte Alessandro 
Published: July 2018

SummaryReceptors for different monoamines, peptides and other neurohormones are present in the plasma membrane of platelets, and the sophisticated process of haemostasis is regulated by the interplay of their physiologic agonists (1). The recent report of a platelet binding* site for phencyclidine (2) suggested a possible role of N-methyl-D-aspartate (NMDA) receptors in platelet function. Isotherms of [3H]-glutamate (GLU), [3H]-CGP-39653, [3H]-glycine (GLY) and [3H]-MK-801 carried out in platelet membranes yielded Bmax and Kd values for these ligands similar to those present in neurons, and NMDA only partially displaced [3H]-GLU. In neurons [3H]-MK-801 binding is potentiated by GLU and/or GLY and, being specific for the open NMDA receptor channel species, it has a functional meaning. In platelet membranes neither GLU and/or GLY increased [3H]-MK-801 binding; thus suggesting that NMDA receptors in platelets are different from those present in neurons. GLU or NMDA alone did not induce platelet aggregation. However, both amino acids were antagonistic on the aggregating activity of arachidonic acid (AA), NMDA being 3 orders of magnitude more active than GLU, and NMDA also antagonized adenosine diphosphate (ADP) and platelet aggregating factor (PAF) induced platelet aggregation. Finally, NMDA increased cAMP levels in intact platelets, and such an effect did not occur in a Ca2+-free medium; yet, cAMP increase was not antagonized by the calmodulin inhibitor trifluoperazine (TFP). It was concluded that platelet membranes carry an NMDA receptor, functionally distinct from the neuronal one, which seems to play an anti-aggregating role.
Magnesium Inhibits Platelet Activity - An In Vitro Study
Authors: Ravn Hanne Berg , Vissinger Henrik , Dalby Kristensen Steen , Elkjcer Husted Steen 
Published: July 2018

SummaryThe in vitro effect of magnesium (Mg) on platelet aggregation and platelet release function was evaluated in healthy volunteers. Platelet aggregation was induced with collagen, ADP, or thrombin after incubation of the sample with saline or increasing concentrations of magnesium sulphate (MgSO4) (0.5-8.0 mM). Mg showed a dose-dependent inhibition of platelet aggregation in whole blood, platelet rich plasma and washed platelets. An antiaggregatory effect was also present with low Mg concentrations. Statistically significant inhibition of the mean aggregation response was obtained in 83% of the different media and agonists tested following the addition of 1.0 mM Mg. The remaining 17% were significantly inhibited with the addition of 2.0 mM Mg. The platelet synthesis of thromboxane A2 and release of beta-thrombo-globulin were also inhibited by Mg, in a dose-dependent manner. In order to evaluate if any of these effects were modified by conventional antithrombotic treatment with low-dose acetylsalicylic acid (ASA), volunteers were asked to meet on two consecutive days. On day 2 the participants were given 300 mg ASA orally, one hour prior to blood sampling. The Mg mediated effects were present independent of this pretreatment with ASA. Following stimulation with collagen a synergistic effect of Mg and ASA was demonstrated on platelet aggregation. The platelet inhibiting effect demonstrated in this study may in part explain the beneficial effect of Mg infusion in some patients with acute myocardial infarction. The effect of Mg infusion, given alone or administered simultaneously with ASA, should also be evaluated in other arterial thrombotic disease states.
Prevention of Early Reocclusion after Thrombolysis of Copper Coil-induced Thrombi in the Canine Carotid Artery: Comparison of PEG-Hirudin and Unfractionated Heparin
Authors: Rübsamen Klaus , Hornberger Wilfried 
Published: July 2018

SummaryCofactor-independent thrombin inhibitors as adjunctive treatment to thrombolysis have been found to enhance reperfusion and reduce the incidence of early reocclusion more effectively than heparins. However, all thrombin inhibitors presently available are rapidly cleared from the circulation which may cause rebound effects after cessation of treatment. To evaluate the effect of PEG-hirudin (LU 87981) a new, long acting derivative of hirudin as adjunctive treatment to rt-PA, a thrombotic occlusion of the carotid artery was induced in mongrel dogs by means of a copper coil. Vessel patency was continuously monitored with an electromagnetic flow probe. Thrombolysis of the occluded artery was induced by administration of 40 Μg × kg−1 + 240 Μg × kg−1 × h−1 rt-PA (low dose) or 80 Μg × kg−1 + 480 Μg × kg−1 × h−1 rt-PA (high dose). With high dose rt-PA treatment, patency was achieved in all animals within 50 min (range 24 to 75), with low dose rt-PA treatment only in 6 out of 8 animals after 73 min (range 26 to 117). Concomitant administration of PEG-hirudin (0.3 mg × kg−1 bolus + 0.15 mg × kg−1 × h−1 infusion) increased the incidence of reperfusion in the low dose rt-PA group to 100% while the reperfusion time was shortened from 73 min in the corresponding control group to 38 min (range 20 to 75 min) in the group given PEG-hirudin (p = 0.065, Mann-Whitney U-test). The carotid artery blood flow, which rapidly declined to zero within 18 to 27 min after discontinuing low or high dose rt-PA infusions remained at a sustained level for the whole observation period of 4 h only in the group given PEG-hirudin. Only one animal reoccluded after 229 min. Unfractionated heparin (UFH) given at a dose of 0.3 mg × kg−1 bolus + 0.3 mg × kg−1 × h−1 infusion did not improve the incidence of reperfusion or lower the incidence of reocclusion. Buccal bleeding time was prolonged after high dose rt-PA treatment and after low dose rt-PA with adjunctive UFH- or PEG-hirudin treatment. Buccal blood loss was not significantly affected by either treatment.In conclusion, these experiments indicate that early reocclusion after thrombolysis can effectively be diminished by concomitant treatment with the long acting thrombin inhibitor PEG-hirudin with moderate effects on bleeding time and aPTT.
New Mutations Causing the Premature Termination of Translation in the A Subunit Gene of Coagulation Factor XIII
Authors: Kangsadalampai Sasichai , Farges-Berth Anne , Hande Çaglayan S , Board Philip G 
Published: July 2018

SummaryThe amplification of factor XIIIA subunit gene exons and heteroduplex analysis has been used to identify two new mutations that cause severe factor XIII deficiency. One mutation in a family of French origin results from a 4 bp deletion and leads to a premature termination of translation. The other mutation occurred in a Turkish family and results from a C → T transition that inserts a premature translation stop signal at codon 400. Both mutations alter restriction enzyme sites and can be readily detected in amplified exon DNA for genetic counselling or prenatal diagnosis. The new mutations reflect the extensive molecular heterogeneity of factor XIII deficiency.
Modulation of Plasma Fibrinogen Levels by Ticlopidine in Healthy Volunteers and Patients with Stable Angina Pectoris
Authors: de Maat Moniek P M , Arnold Alf E R , Buuren Stef van , Paul Wilson J H , Kluft Cornells 
Published: July 2018

SummaryElevated plasma fibrinogen levels are associated with an increased risk for cardiac events. Ticlopidine is a drug that inhibits the ADP-induced aggregation of blood platelets and it also has been described that ticlopidine can decrease the plasma fibrinogen level in patients with vascular diseases. The mechanism of this decrease has not yet been elucidated and therefore mechanisms that are known to affect fibrinogen levels were studied, viz. the acute phase reaction, total fibrin plus fibrinogen degradation (TDP) levels and the polymorphisms of the fibrinogen β-gene.The fibrinogen lowering effect of ticlopidine was studied in 26 healthy volunteers, selected on genotype of the BclI polymorphism of the fibrinogen β-gene, and in 26 patients with stable angina pectoris in a double blind, randomized cross-over study. Functional plasma fibrinogen levels were measured with the Clauss assay. Fibrinogen antigen, C-reactive protein (CRP) and TDP levels were measured using an enzyme immuno assay (EIA).In the healthy volunteers the functional fibrinogen levels had decreased by 0.20 g/l (9%, p = 0.005 using the paired Student t-test) after 4 weeks of 250 mg bid ticlopidine administration, whereas fibrinogen antigen, CRP and TDP levels were not significantly changed. In the stable angina pectoris patients the pre-treatment fibrinogen, CRP and TDP levels were significantly higher than in the volunteer group. After four weeks 250 mg bid ticlopidine administration the functional fibrinogen levels had decreased by 0.38 g/l (11%, p < 0.005), whereas the fibrinogen antigen, CRP and TDP levels were not significantly changed. The levels of functional and antigen fibrinogen, CRP and TDP did not change significantly during the placebo period in the volunteers or the patients. Neither in the volunteers nor in the patients was the effect of ticlopidine on the fibrinogen levels associated with the fibrinogen β-gene polymorphisms.Therefore, the fibrinogen lowering effect of ticlopidine is likely to be a modulation of the functionality of the molecule and unlikely to be modulated by the acute phase reaction, TDP-levels or the fibrinogen β-gene polymorphisms.
Association between High Values of D-dimer and Tissue-plasminogen Activator Activity and First Gastrointestinal Bleeding in Cirrhotic Patients
Authors: Violi Francesco , Basili Stefania , Ferro Domenico , Quintarelli Claudio , Alessandri Cesare , Cordova Corrado ,   CALC Group
Published: July 2018

SummaryCirrhotic patients with decompensated state and high serum levels of fibrin(ogen) degradation products are at high risk of bleeding. The aim of this study was to further analyse the relationship between hyperfibrinolysis and bleeding in cirrhosis by measuring plasma values of D-dimer and tissue plasminogen activator (t-PA) activity. One-hundred-twelve cirrhotic patients with oesophageal varices and without previous upper-gastrointestinal bleeding entered the study and were followed-up for 3 years. Patients were considered to have hyperfibrinolysis if they concomitantly had high values of D-dimer and t-PA activity. During the follow-up 34 (30%) patients bled. They had more severe liver failure (p = 0.0001) and variceal size (p = 0.0031) and higher prevalence of ascites (p = 0.0003), varices with red signs and hyperfibrinolysis (p = 0.0001) than patients who did not bleed. Multivariate analysis disclosed hyperfibrinolysis as the only marker predictive of bleeding (Hazard Ratio = 42.5, p <0.001). Our findings suggest that screening for hyperfibrinolysis may be useful to identify cirrhotic patients at risk of bleeding.
An Alternative Elastase-mediated Degradation of Fibrinogen and Fibrin Observed in a Patient with Herpes Simplex Encephalitis and Pneumonia
Authors: lijima Kenji , Murakami Fumiyo , Horie Yasushi , Nakamura Katsumi , Ikawa Shiro , Soe Gilbu , Kohno Isao , Nakayasu Hiroyuki , Shimomura Tokio , Takahashi Kazuro 
Published: July 2018

SummaryA 74-year-old female developed pneumonia following herpes simplex encephalitis. Her white blood cell counts reached 28,400/μl, about 90% of which consisted of granulocytes. The polymorphonuclear (PMN) elastase/α1-arantitrypsin complex levels increased and reached the maximum of 5,019 ng/ml, indicating the release of a large amount of elastase derived from the granulocytes. The mechanism of PMN elastase release was most likely to be granulocyte destruction associated with phagocytosis. The cleavage of fibrinogen and fibrin by PMN elastase, independent of plasmin, was indicated by the presence of the fragments in immunoprecipitated plasma from the patient corresponding to elastase-induced FDP D and DD fragments and the absence of fragments corresponding to plasmin-induced FDP D and DD fragments on SDS-PAGE. These findings suggested that the large amount of PMN elastase released from the excessive numbers of granulocytes in this patient with herpes simplex encephalitis and pneumonia, induced the cleavage of fibrinogen and fibrin without the participation of plasmin.
The Propeptides of Human Protein C, Factor VII, and Factor IX Are Exchangeable with Regard to Directing Gamma-Carboxylation of these Proteins
Authors: Geng Jie-Ping , Castellino Francis J 
Published: July 2018

SummaryThe specificity of the propeptide sequence in directing vitamin Independent post-translational γ-carboxylation has been assessed by examination of the extent of processing of chimeric constructs of blood coagulation factor VII (fVII), factor IX (fIX) and protein C (PC). One chimera consisted of a protein in which the γ-carboxyglutamic acid (Gla)/helical stack domain of PC (amino acid residues 1 to 46) was replaced by that of fIX (residues 1 to 47) in an otherwise intact PC. Another consisted of the same construction of a fVII/PC Gla domain-based mutant protein. The final chimera contained the leader/propeptide sequence of PC (residues -42 to -1) replaced by that of fIX (residues -46 to -1). In each case, all Glu-precursor Gla residues in the Gla domains of the proteins were fully processed to Gla. These results demonstrate that the propeptides of fIX and PC are capable of directing γ-carboxylation of the Gla regions of either protein, that the propeptide of PC can fully function in γ-carboxylation of the Gla region of fVII, and further suggest that, with regard to γ-carboxylation, communications between the propeptides and Gla domains in intact proteins are general in nature.
β2 Glycoprotein-I Inhibits Factor XII Activation on Triglyceride Rich Lipoproteins: The Effect of Antibodies from Plasma of Patients with Antiphospholipid Syndrome
Authors: McNally T , Mackie I J , Isenberg D A , Machin S J 
Published: July 2018

SummaryIt is now well recognised that antiphospholipid antibodies are associated with thrombosis and recurrent fetal loss. Some antiphospholipid antibodies (aPAs) have been shown to require a cofactor, β2 glyco-protein-I (β2GPI), for binding to phospholipids, and recently β2GPI has been identified as the antigenic target for some aPAs. β2GPI possesses in vitro anticoagulant properties and modulation of β2GPI function may therefore result in altered haemostatic regulation. In the present study, the influence of plasma derived aPAs and β2GPI on factor XII activation on the surface of very low density lipoprotein (VLDL) was investigated. Factor XIIa generation was dependent on lipoprotein lipase treatment of VLDL and β2GPI inhibited the factor XIIa generation in a concentration dependent manner. No consistent effects on factor XIIa generation were demonstrated with the IgG fractions from patients with aPAs. Inhibition of the β2GPI activity was demonstrated by some antibodies, and study with cardiolipin affinity purified antibody indicated that antibody concentration is critical. These results suggest that perturbation of β2GPI function may contribute to the pathogenic mechanism for thrombosis in some patients with aPAs. .
Non Neutralizing Antibodies to Tissue Type Plasminogen Activator in the Serum of Acute Myocardial Infarction Patients Treated with the Recombinant Protein
Authors: Cugno Massimo , Cicardi Marco , Colucci Mario , Bisiani Giuliana , Angelica Merlini Piera , Spinola Alessandra , Paonessa Raffaella , Agostoni Angelo 
Published: July 2018

SummaryRecombinant tissue-type plasminogen activator (rt-PA) is currently used as a thrombolytic agent in the management of acute myocardial infarction (AMI). Since it is known that other recombinant proteins induce antibody formation when administered to humans, we determined the presence of anti-rt-PA antibodies in serial blood samples from 60 AMI patients (43 treated with and 17 without rt-PA). Blood samples were taken upon hospital admission, 15 days and 1, 3,6 months thereafter. A blood sample was also collected from 200 healthy subjects. Using an ELISA, anti-rt-PA antibodies were detected as serum immunoglobulins specifically binding immobilized rt-PA. AMI patients before treatment and normal subjects exhibited negligible levels of anti-rt-PA antibodies; both groups had only one outlier value. Fifteen days after rt-PA treatment, 2 AMI patients showed an increase in antibody titer beyond the highest normal value. This titer progressively decreased during the following 6 months. The antibodies from these two patients bound rt-PA both in a solid and fluid phase. They bound melanoma t-PA to a lower degree and did not bind urokinase type plasminogen activator at all, indicating specificity for t-PA. The marked temporal relationship between rt-PA infusion and antibody appearance indicated that antibody formation had been elicited by the infusion of rt-PA. Nevertheless, the lack of anti-rt-PA antibody interference with rt-PA function in vitro, along with the favourable clinical outcome of those patients having such antibodies would indicate that the appearance of anti-rt-PA antibodies does not interfere with the physiological fibrinolytic activity.
Neointima Formation in Injured Hamster Carotid Artery Is Effectively Prevented by the Combination G4120 and Quinapril
Authors: Matsuno Hiroyuki , Marie Stassen Jean , Moons Lieve , Vermylen Jos , Hoylaerts Marc F 
Published: July 2018

SummaryThe prevention of neointima formation by the tissue selective angiotensin converting enzyme (ACE) inhibitor quinapril and by the combination quinapril/G4120 (a platelet αIIbβ3 and smooth muscle cell αvβ3 antagonist) was investigated in a hamster carotid artery injury model. Quinapril at 10 mg/kg/day reduced neointima formation by about 45%, 1 and 2 weeks after injury to the artery, i.e. significantly better than the non-tissue selective ACE inhibitor captopril at 100 mg/kg/day. Quinapril did not decrease the early smooth muscle cell (SMC) proliferation in the media, but in agreement with its inhibition of the carotid artery ACE activity by 62%, SMC proliferation was reduced by 70% in the newly forming intima. To improve the inhibition of early medial SMC proliferation, quinapril (10 mg/kg/day) was complemented with G4120 (100 Μg/kg/h). This combined treatment reduced the proliferation of medial SMCs to about 50% throughout the first week following injury, whereas intima SMC proliferation was reduced by 70% throughout treatment. Accordingly, the drug combination reduced neointima formation more potently than each drug separately by 70%. The disruption of medial elastic laminae, observed in the control and G4120 treated group, was consistently reduced when G4120 was complemented with quinapril. Thus, the present study shows in a hamster model of carotid artery injury, that combining drugs that prevent SMC migration and proliferation via different modes of action can lead to the effective prevention of neointima formation.
Two Recombinant Tissue Factor Reagents Compared to Conventional Thromboplastins for Determination of International Normalised Ratio: A Thirty-three-laboratory Collaborative Study
Authors: Kitchen S , Jennings I , Woods T A L , Walker I D , Preston F E ,   On behalf of the Steering Committee of the UK National External Quality Assessment Scheme for Blood Coagulation
Published: July 2018

SummaryRecent advances in recombinant technology have led to the development of prothrombin time (PT) reagents containing recombinant tissue factor which has been lipidated to allow expression of procoagulant activity. In this study we have compared International Normalised Ratios (INRs) determined using two such reagents and conventional thromboplastins in widespread use in the UK.Lyophilised plasma samples from eight different warfarinised patients were distributed to 33 laboratories in the UK. Each participant determined prothrombin times on 20 local fresh normal plasmas (used to derive mean normal PT and calculate INR) and the eight lyophilised samples, using manual technique and the following thromboplastins; Recombiplastin (Ortho Diagnostics Ltd); Innovin (Baxter Diagnostics Ltd); the conventional thromboplastin in local use.For eight plasmas the mean INRs determined with different reagents were as follows: Innovin (33 laboratories) - 3.4; Manchester Reagent (MR = 8 laboratories) - 3.4; Recombiplastin (33 laboratories) - 3.7; Instrumentation Laboratory (IL = 13 laboratories) - 4.4.Mean INR results with Recombiplastin were on average 7% greater than those obtained with Innovin, 8% greater than results with MR and 18% less than INRs with IL thromboplastin. There was no significant difference between results obtained with Innovin and MR. In contrast INRs obtained with IL were markedly (mean 28%) greater than results obtained with Innovin.This study employed lyophilised plasma and it is possible that some of the relationships described are influenced by this. However, the lyo-philisation process employed did not influence the relationship between INRs of warfarinised plasmas obtained by the four main reagents described, indicating that the results are relevant to routine clinical practice.In conclusion, our data show some important differences are present between INRs determined using Recombiplastin, Innovin and two conventional thromboplastins.