bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Recombinant Hirudin in Hemodialyzed End-stage Renal Failure Patients
Authors: Vanholder R , Camez A , Veys N , Loo A Van , Dhondt A M , Ringoir S 
Published: July 2018

SummaryRecently, hirudin was used for the first time as an anticoagulant during hemodialysis in men. Pharmacokinetic data of this compound in end-stage renal failure are however not available. In this study, the pharmacokinetics of recombinant hirudin (HBW 023) was evaluated in hemodialysis-treated end-stage renal failure patients. HBW 023 was administered as a bolus at the start of a single dialysis (0.02 to 0.08 mg/kg) in 20 patients, and plasma hirudin levels were followed during this and the 5 following dialyses, without additional hirudin administration. The initial dialysis (HDj) was performed with a low flux polysulfone dialyzer; the following dialyses (up to HD6) with a high flux polysulfone dialyzer and regular heparin. Hirudin levels averaged 504.0 ± 214.0 and 527.7 ± 217.1 ng/ml in the middle and at the end of HDj, and then gradually decreased to 15.2 ± 15.2 ng/ml at the end of HD6. Pharmacokinetic data were compared to those obtained in healthy controls (n = 5), receiving the same dose, and reaching the same peak hirudin level. Hirudin half-life was >30 times longer in hemodialysis patients (51.8 ± 15.6 vs. 1.7 ± 1.5 h, p <0.001), whereas area under the curve was >60 times higher (34,669 ± 14,898 vs. 545 ± 205 ng/ml X h, p <0.001). Distribution volume was lower in hemodialysis patients (11.0 ± 3.1 vs. 14.1 ± 2.0 1, p <0.05). Hirudin disappearance rate was the same during high flux polysulfone dialysis as during interdialytic periods. Hirudin removal was markedly higher in those patients still maintaining some residual renal function and parameters of hirudin removal were significantly correlated to residual creatinine clearance. It is concluded that hirudin removal from the body is markedly depressed in hemodialyzed end-stage renal failure patients and that even minor residual renal function may increase this removal rate.
Anti-factor VIII Inhibitors and Lupus Anticoagulants in Haemophilia A Patients
Authors: Blanco Alicia N , Cardozo María A , Candela Miguel , Santarelli María T , Bianco Raúl Pérez , Lazzari María A 
Published: July 2018

SummaryIn a study of 170 haemophilia A patients, 43 were found to have an inhibitory effect; seven had anti-factor VIII inhibitors (a-fVIII) (A), 18 had lupus anticoagulants (LAs) with a strong (B: 12) or weak (C: 6) time-dependent effect and 18 had no time-dependent LAs (D). The a-fVIII showed a neutralizing effect only against factor VIII and negative diluted Russell viper venom time (dRVVT). The LAs were diagnosed by dRVVT; the Staclot® LA agreed with the dRVVT. During the study, three patients changed from an a-fVIII to an LA pattern; they also modified their clinical response.Our prevalence of a-fVIII was low (4%) and we found 21% of LA, with a high (50%) prevalence of time-dependent inhibition. This pattern raises the possibility of the coexistence of LA and a-fVIII, stressing the need to develop specific tests to identify a-fVIII and LA.
Anticoagulant Properties of Rabbit Lungs in Tissue Thromboplastin-induced Intravascular Coagulation
Authors: Vad Henrik , Tvedskov Tove F , Hansen Knud B , Albrechtsen Ole K , Jespersen Jørgen , Gram Jørgen 
Published: July 2018

SummaryThis study was conducted in order to examine possible anticoagulant properties of the lungs during tissue thromboplastin-induced intravascular coagulation. Rabbit brain tissue thromboplastin (n = 17) or saline (n = 6 + 3) was infused above the right atrium (n = 11 + 3) of the heart or in the arcus aorta (n = 6) for a period of 120 min in non-pregnant New Zealand rabbits. Rabbits infused with tissue thromboplastin responded with significantly (p <0.05) more excessive changes in a number of haemodynamic variables (heart rate, paO2> paCO2, blood pH etc.) compared with rabbits infused with saline.Similarly, the prothrombin time (p <0.05) and the activated partial thromboplastin time (p <0.05) were significantly more prolonged in rabbits receiving tissue thromboplastin compared with control animals. Also the concentration of blood platelets (p<0.05), plasma fibrinogen (p <0.05), antithrombin (p <0.05), and protein C (p <0.05) decreased significantly in thromboplastin-treated animals compared with control animals. In all these haemostatic variables there was a common trend that animals infused with tissue thromboplastin in the arcus aorta responded more excessively than animals infused in the right atrium of the heart, and these deviations were statistically significant for fibrinogen (p <0.05) and prothrombin time (p <0.05). Similarly, animals infused with tissue thromboplastin in the arcus aorta had an increased number of microthrombi in the lungs and kidneys compared with animals receiving tissue thromboplastin above the right atrium.As the lungs are the first pass organ when you infuse above the right atrium the results from this study suggest that the lungs play a key role in protecting the organism against excessive tissue thromboplastin-induced activation of coagulation.
Inhibition rather than Enhancement of Hemostatic System Activation during Initiation of Oral Anticoagulant Treatment
Authors: Kyrle Paul A , Brockmeier Johannes , Weltermann Ansgar , Eichinger Sabine , Speiser Wolfgang , Lechner Klaus , Eichler Hans-Georg 
Published: July 2018

SummaryCoumarin-induced skin necrosis is believed to be due to a transient hypercoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X during initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a technique that investigates coagulation activation in the microcirculation.We determined in 10 healthy volunteers the concentrations of prothrombin fragment F1+2 (f1.2) and thrombin-antithrombin complex (TAT) in blood emerging from an injury of the microvasculature (bleeding time incision) before and after initiation of both high-inten- sity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F Vila) and the activities of FII, F VII, F X and protein C were measured in venous blood.A rapid decline of F VII and protein C was observed in venous blood with activities at 24 h of 7 ± 1% and 43 ± 2%, respectively, during the high-intensity regimen. A 20 to 30% reduction of f1.2 and TAT was seen in venous blood at 72 h with no major difference between the high- and the low-intensity regimen. F Vila levels were substantially affected by anticoagulation with a >90% reduction at 48 h during the high-intensity regimen. Following high-intensity coumarin, a >50% decrease in the fl.2 and TAT levels was found in shed blood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT levels was seen neither in shed blood nor in venous blood.Our data do not support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-induced skin nekrosis.
Modulation of Blood Cell Activation by Four Commonly Used Anticoagulants
Authors: Engstad Charlotte Sissener , Gutteberg Tore Jarl , Østerud Bjarne 
Published: July 2018

SummaryIn the past years, our group has made several observations suggesting that blood cells behave differently and when stimulated, release different levels of cytokines, depending on which anticoagulant the blood has been drawn into. The aim of this study was therefore to compare the effect of the four anticoagulants EDTA, citrate, heparin and hirudin on monocyte, neutrophil (PMN), and platelet function in human whole blood. Human whole blood was employed as an ex vivo model of cytokine production and protein secretion, and lipopolysaccharide (LPS) induced tissue factor (TF) activity in monocytes and LPS induced tumor necrosis factor α (TNFα) release were chosen as parameters of monocyte activation. Platelet factor 4 (PF4) secretion and LPS induced lacto ferrin release were chosen as parameters of platelet and PMN activation, respectively. When human whole blood was stimulated with 5 ng/ml LPS for 2 h, TF activity in monocytes isolated from EDTA blood was found to be 2.9 mU/106 cells, whereas TF activity in monocytes isolated from citrated, heparinized and hirudinized blood was 14.7, 24.7 and 28.5 mU/106 cells, respectively. TNFα concentrations in platelet poor plasma (PPP) isolated from whole blood stimulated with 5 ng/ml LPS for 2 h was increased with 200,400 and 350% in citrated, heparinized and hirudinized blood respectively, as compared to EDTA blood. Next, the effect of the anticoagulant on PMN secretion was measured. PPP isolated from whole blood incubated with 5 ng/ml LPS for 90 min contained 1170 ng/ml (EDTA blood), 2880 ng/ml (citrated blood), 4220 ng/ml (heparinized blood), and 5520 ng/ml lactoferrin (hirudinized blood). When studying the platelet parameter PF4, whole blood was incubated without any stimuli for 60 min, and we found that heparin PPP contained 1180 ng/ml PF4, while hirudin PPP contained 469 ng/ml, citrate PPP 440 ng/ml, and EDTA PPP 217 ng/ml PF4, respectively. Finally, the low molecular weight heparin compound Fragmin had no enhancing effect on PF4 levels in whole blood. It is concluded that the anticoagulant used in in vitro experiments has a large influence on the parameters measured.
Thrombin Generation Markers and Coronary Heart Disease Risk Factors in a Polish Population Sample
Authors: Musiał Jacek , Pająk Andrzej , undas Anetta , Kawalec Ewa , Topór-Mądry Roman , Pażucha Tadeusz , Grzywacz Marek , Szczeklik Andrzej 
Published: July 2018

SummaryThrombosis plays a major role in the development of atherosclerosis and its acute vascular complications. Epidemiological studies have shown that elevated levels of plasma fibrinogen are associated with an increased risk of coronary heart disease (CHD). It is not clear whether this association is linked to hemostatic functions of fibrinogen which serves as a substrate for thrombin. Generation of thrombin in vivo can be evaluated by measurement of its specific markers in plasma, i.e. thrombin-antithrombin III complex (TAT) and prothrombin fragment 1+2 (F1+2). We determined plasma levels of TAT and F1+2 in a population sample of southeastern Poland and evaluated relations of these markers with plasma fibrinogen, factor VII coagulant activity (FVIIc), and other known CHD risk factors. The population studied consisted of 215 men and 251 women, aged 43-75 years. Final analysis was performed on 195 men and 222 women.The distribution of plasma TAT and F1+2 concentrations were highly skewed with the higher median values for women than for men. Log values of TAT correlated with log values of F1+2 in men (r = 0.27, p <0.01) and in women (r = 0.15, p <0.05). In the regression analysis both markers were positively related to age in women but not in men. After adjustment to age there was a positive relation between TAT and fibrinogen in both sexes. In women, but not in men, F1+2 showed a positive association with FVIIc. Total plasma cholesterol was negatively related to TAT in women only. There was no association between thrombin generation markers and plasma triglycerides, HDL-choles- terol, LDL-cholesterol, blood pressure, cigarette smoking and body mass index (BMI).The association of plasma fibrinogen and FVIIc with thrombin generation markers points to an important role of the hemostatic system in the pathogenesis of atherosclerosis and coronary heart disease in humans.
Thrombin Interaction with Platelet GPIB: Role of the Heparin Binding Domain
Authors: De Candia Erica , De Cristofaro Raimondo , De Marco Lulgi , Mazzucato Moreno , Picozzi Matilde , Landolfi Raffaele 
Published: July 2018

SummaryThe platelet membrane glycoprotein lb (Gplb) has a high affinity binding site for α-thrombin whose occupancy is thought to positively modulate the thrombin-induced platelet activation. In this study, aimed at further characterizing the thrombin-GpIb interaction, two thrombin anion exosites referred to as “heparin binding site” (HBS) and “fibrino#gen recognition site” (FRS) were investigated as the possible domains involved in Gplb binding. The role of thrombin HBS was explored by performing binding measurements of 125I-α-thrombin to purified glycocalicin (GC), the extracytoplasmic portion of Gplb, in the presence of heparin as well as after chemical modifications of the thrombin heparin binding site (thrombin-HBS phosphopyridoxylation). These studies showed that a) thrombin binding to GC could be competitively inhibited by heparin and b) the equilibrium association constant for thrombin-GC interaction was reduced up to ten-fold by chemical modifications at the HBS. On the other hand, the role of FRS in the thrombin-GC interaction could be excluded by other experiments showing that GC in solution could not influence the interaction of α-thrombin with two substrates which bind to both the catalytic site and the fibrinogen recognition site: 1) the thrombin receptor peptide 38-60 (TR, L38-E60) and 2) the A α-chain of fibrinogen. Altogether these results demonstrated that GC interaction with thrombin involves the enzyme heparin binding site, whereas the fibrinogen recognition site does not play a significant role.
CD1lb/CD 18 Mediates the Neutrophil Chemotactic Activity of Fibrin Degradation Product D Domain
Authors: Gross Thomas J , Leavell Keith J , Peterson Michael W 
Published: July 2018

SummaryCoagulation and fibrinolysis universally accompany tissue injury and repair. The accumulation of regionally generated fibrin degradation products (FDP) may modify the local inflammatory response. We have found FDP to be potent neutrophil chemotaxins. We separated plasmin FDP by chromatofocusing and found chemotactic activity limited to fractions containing the fibrinogen D domain (D-D dimer and D monomer). The bioactivity of the D-D dimer did not require an intact cross link site as removal of this sequence with puff adder venom or hypocalcemic plasmic digestion did not decrease chemotaxis. Peptide inhibition studies confirmed that the chemotactic region did not involve terminal gamma chain sequences or alpha chain RGD motifs. The internal gamma chain peptide KYGWTVFQKRLDGSV (PI), known to bind CDllb/CD18, exhibited concentration dependent chemotactic activity. Similarly, monoclonal antibodies directed against CD1lb/CD18 blocked PMN migration to FDP without similar inhibition of chemotaxis to IL-8 or LTB4. Thus, neutrophil chemotaxis to FDP is mediated by interactions between the fibrinogen D domain and CD1lb/CD18.
The Coagulation and Fibrinolytic Responses of Baboons after In Vivo Thrombin Generation – Effect of Interleukin 6
Authors: Kruithof Egbert K O , Mestries Jean Claude , Gascon Marie-Paule , Ythier Arnaud 
Published: July 2018

SummaryDisseminated intravascular coagulation (DIC) may lead to severe thrombotic or hemorrhagic complications. The present work was undertaken to study the effect of interleukin 6 (IL-6) on variations of key coagulation and fibrinolytic parameters in plasma in a baboon model of experimental DIC induced by injection of factor Xa and phospholipids at dosages leading to partial (48%) or complete fibrinogen depletion. Transient increases of D-dimer, fibrinopeptide A, thrombin-antithrombin and the activated partial thromboplastin time were observed. Each parameter had a particular (time and Xa/phospho- lipid dose dependent) pattern of changes. The principal effect of IL-6 was a more rapid restoration of fibrinogen concentrations and of overall coagulation tests. Injection of factor Xa/phospholipids led also to a rapid increase of tissue-type plasminogen activator (t-PA) the extent of which was dependent on Xa/phospholipid dose. Pretreatment with IL-6 induced a threefold increase of basal t-PA and a corresponding increase of the t-PA response. Plasminogen activator inhibitor type 1 (PAI-1) concentrations did not change after low dose Xa/phospholipids, but increased eightfold after high dose Xa/phospholipids. IL-6 pretreatment induced within 8 h a twentyfold increase of PAI-1 but no further increase was observed after injection of factor Xa/phospholipids.Thus, in vivo thrombin generation leads to dynamic modifications of the coagulation and fibrinolytic systems. The principal effect of IL-6 is a more rapid normalization of overall coagulation tests, due to normalization of fibrinogen, and an increased t-PA release response which is partially counteracted by increased PAI-1 concentrations.
Aggregation of Human Blood Platelets by Remnant Like Lipoprotein Particles of Plasma Chylomicrons and Very Low Density Lipoproteins
Authors: Saniabadi Abby R , Umemura Kazou , Shimoyama Makiko , Adachi Masakazu , Nakano Minoru , Nakashima Mitsuyoshi 
Published: July 2018

SummaryRemnant like lipoprotein particles (RLP) of partially catabolised human plasma chylomicrons (CM) and very low density lipoproteins (VLDL) were separated from CM and VLDL using two monoclonal antibodies, anti apo B-100 (JI-H) and anti apo A-I (H-12) coupled to Sepharose 4B gel to form an immunoaffinity column. Lipoproteins containing apo B-100 or apo E, including VLDL and LDL adsorb to (JI-H)-gel, while CM and HDL with apo A-I adsorb to (H-12)-gel. The unbound fraction (RLP) is rich in apo B-48, apo E and apo E rich apo B-100 which has not been recognized by JI-H. The RLP fraction with a total triglyceride of 12.35 ± 6.22 mg/ml; total cholesterol, 0.32 ± 0.08 mg/ml and total protein, 0.72 ± 0.12 mg/ml (mean ± S.E.M, n = 9) was added to blood from healthy persons at 2.5-200 |xl/ml and agitated gently at 37° C for 40 s. Platelet aggregation was assessed by measuring the loss of single platelets. At 2.5-10 μl, RLP induced platelet aggegation increased with the dose of RLP, but decreased at 25-200
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Scanning electron microscopy revealed that within 20 s of agitation in the presence of RLP, activated platelets had appeared on the red cell membrane and within 40 s of agitation, platelet aggregates had formed on the red cells. The platelet responses were unaffected by aspirin (10 or 20 μg/ml) but were inhibited by cilostazol, a phosphodiesterase type III inhibitor (0.4 to 1.6 μg/ml). It is likely that the platelet effect of RLP is a consequence of RLP dependent red cell-platelet interaction. This is the first report of platelet aggregation induced by RLP without an added platelet agonist.
Prognostic Evaluation of Mortality after Pediatric Resuscitation Assisted by Extracorporeal Life Support
Authors: De Mul Aurélie , Nguyen Duy-Anh , Doell Carsten , Perez Marie-Hélène , Cannizzaro Vincenzo , Karam Oliver 
Published: July 2018

AbstractTo improve survival rates during cardiopulmonary resuscitation (CPR), some patients are put on extracorporeal life support (ECLS) during active resuscitation (ECPR). Our objective was to assess the clinical outcomes after pediatric ECPR in Switzerland and to determine pre-ECPR prognostic factors for mortality. The present study is a retrospective analysis. The study setting included three pediatric intensive care units in Switzerland that use ECPR. All patients (<16 years old) undergoing ECPR from 2008 to 2016 were included in the study. There were no interventions. Data before ECLS initiation and clinical outcomes were collected. An ECPR score was designed to predict mortality, based on variables significantly different between survivors and non-survivors. Fifty-five patients were included, with a median age of 13.5 months. Eighty percent were cardiac patients. The mortality rate was 75%. Mortality was significantly associated with CPR duration (p = 0.02), last lactate (p = 0.05), and last pH (p = 0.01) before ECLS initiation. Based on these three variables, an ECPR score was designed as follows: CPR duration (in minutes): 1 point if < 40; 2 points if ≥ 40; 3 points if ≥ 60; 6 points if ≥ 105. Lactate (in mmol/L): 1 point if < 8; 2 points if ≥ 8; 3 points if ≥ 14; 6 points if ≥ 18. pH: 1 point if > 7.00; 2 points if ≤ 7.00; 3 points if ≤ 6.85; 6 points if ≤ 6.60. The area under the receiver-operating characteristic curve was 0.74. The positive predictive value of a score ≥ 9 was 94%. In our population, a score based on three variables easily available prior to ECLS initiation had good discrimination and could appropriately predict mortality. This score now needs validation in a larger population.
CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function
Authors: Bandala-Sanchez Esther , G. Bediaga Naiara , Goddard-Borger Ethan D. , Ngui Katrina , Naselli Gaetano , Stone Natalie L. , Neale Alana M. , Pearce Lesley A. , Wardak Ahmad , Czabotar Peter , Haselhorst Thomas , Maggioni Andrea , Hartley-Tassell Lauren A. , Adams Timothy E. , Harrison Leonard C. 
Published: July 2018

Significance
Inflammation is a protective response of the body’s immune system against harmful stimuli such as pathogenic microorganisms, toxins, or damaged cells. However, if excessive or prolonged, inflammation may be harmful and therefore has to be regulated. Soluble CD52 is a natural sialoglycopeptide and immune regulator that suppresses inflammatory responses. We elucidated the mechanism of this effect by showing that soluble CD52 first sequesters a mediator of inflammation called HMGB1; in turn, this promotes binding of the sialylated CD52 glycan to an inhibitory receptor, sialic acid-binding immunoglobulin-like lectin (Siglec)-10, present on activated T cells and other immune cells. This concerted antiinflammatory mechanism driven by soluble CD52 may contribute to immune-inflammatory homeostasis and underscores the therapeutic potential of soluble CD52.
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
Authors: Sharma Subhalakshmi , Čermáková Kateřina , De Rijck Jan , Demeulemeester Jonas , Fábry Milan , El Ashkar Sara , Van Belle Siska , Lepšík Martin , Tesina Petr , Duchoslav Vojtěch , Novák Petr , Hubálek Martin , Srb Pavel , Christ Frauke , Řezáčová Pavlína , Hodges H. Courtney , Debyser Zeger , Veverka Václav 
Published: July 2018

Significance
The transcription coactivator LEDGF/p75 contributes to regulation of gene expression by tethering other factors to actively transcribed genes on chromatin. Its chromatin-tethering activity is hijacked in two important disease settings, HIV and mixed-lineage leukemia; however, the basis for the biological regulation of LEDGF/p75’s interaction to binding partners has remained unknown. This has represented a gap in our understanding of LEDGF/p75’s fundamental biological function and a major limitation for development of therapeutic targeting of LEDGF/p75 in human disease. Our work provides a mechanistic understanding of how the lens epithelium-derived growth factor interaction network is regulated at the molecular level.
From dimers to webs
Authors: Fraser Chris , Lam Thomas , Le Ian 
Published: July 2018

We formulate a higher-rank version of the boundary measurement map for weighted planar bipartite networks in the disk. It sends a network to a linear combination of

S
L

r

\mathrm {SL}_r

-webs and is built upon the

r
r

-fold dimer model on the network. When

r
r

equals 1, our map is a reformulation of Postnikov’s boundary measurement used to coordinatize positroid strata. When

r
r

equals 2 or 3, it is a reformulation of the

S
L

2

\mathrm {SL}_2

- and

S
L

3

\mathrm {SL}_3

-web immanants defined by the second author. The basic result is that the higher-rank map factors through Postnikov’s map. As an application, we deduce generators and relations for the space of

S
L

r

\mathrm {SL}_r

-webs, re-proving a result of Cautis-Kamnitzer-Morrison. We establish compatibility between our map and restriction to positroid strata and thus between webs and total positivity.