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"Contact pathway"

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https://www.readbyqxmd.com/read/28738274/discovery-and-assessment-of-water-soluble-coumarins-as-inhibitors-of-the-coagulation-contact-pathway
#1
Charlotte Bouckaert, Shu Zhu, José W P Govers-Riemslag, Maxime Depoorter, Scott L Diamond, Lionel Pochet
Over the last decade, the coagulation factor XIIa (FXIIa) has seen renewed interest as a therapeutic target. Indeed, its inhibition could offer a protection against thrombosis without increasing the risk of bleeding. Moreover, it could answer the need for a safe prevention of blood-contacting medical devices-related thrombosis. Among the FXII and FXIIa inhibitors already described in literature, organic small-molecular-weight inhibitors are rather left behind. In this study, we were focused on the discovery and assessment of water soluble small molecules...
July 19, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28576714/alginate-microbeads-are-coagulation-compatible-while-alginate-microcapsules-activate-coagulation-secondary-to-complement-or-directly-through-fxii
#2
Caroline Gravastrand, Shamal Hamad, Hilde Fure, Bjørg Steinkjer, Liv Ryan, Josè Oberholzer, John D Lambris, Igor Lacík, Tom Eirik Mollnes, Terje Espevik, Ole-Lars Brekke, Anne Mari Rokstad
Alginate microspheres are presently under evaluation for future cell-based therapy. Their ability to induce harmful host reactions needs to be identified for developing the most suitable devices and efficient prevention strategies. We used a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbeads (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules)...
May 30, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28338598/characterization-of-distinct-coagulopathic-phenotypes-in-injury-pathway-specific-drivers-and-implications-for-individualized-treatment
#3
S Ariane Christie, Lucy Z Kornblith, Benjamin M Howard, Amanda S Conroy, Ryan C Kunitake, Mary F Nelson, Carolyn M Hendrickson, Carolyn S Calfee, Rachael A Callcut, Mitchell Jay Cohen
BACKGROUND: International normalized ratio (INR) and partial thromboplastin time (PTT) are used interchangeably to diagnose acute traumatic coagulopathy but reflect disparate activation pathways. In this study, we identified injury/patient characteristics and coagulation factors that drive contact pathway, tissue factor pathway (TF), and common pathway dysfunction by examining injured patients with discordant coagulopathies. We hypothesized that patients with INR/PTT discordance reflect differing phenotypes representing contact versus tissue factor pathway perturbations and that characterization will provide targets to guide individualized resuscitation...
June 2017: Journal of Trauma and Acute Care Surgery
https://www.readbyqxmd.com/read/28287584/a-microfluidic-flow-chamber-model-for-platelet-transfusion-and-hemostasis-measures-platelet-deposition-and-fibrin-formation-in-real-time
#4
Katrijn R Six, Rosalie Devloo, Britt Van Aelst, Philippe Vandekerckhove, Hendrik B Feys, Veerle Compernolle
Microfluidic models of hemostasis assess platelet function under conditions of hydrodynamic shear, but in the presence of anticoagulants, this analysis is restricted to platelet deposition only. The intricate relationship between Ca(2+)-dependent coagulation and platelet function requires careful and controlled recalcification of blood prior to analysis. Our setup uses a Y-shaped mixing channel, which supplies concentrated Ca(2+)/Mg(2+) buffer to flowing blood just prior to perfusion, enabling rapid recalcification without sample stasis...
February 14, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28286749/factors-xi-and-xii-as-targets-for-new-anticoagulants
#5
REVIEW
Jeffrey I Weitz, James C Fredenburgh
Compared with vitamin K antagonists, the direct oral anticoagulants (DOACs) are simpler to administer and are associated with less intracranial bleeding. Nonetheless, even with the DOACs, bleeding still occurs and many patients with atrial fibrillation fail to receive anticoagulant thromboprophylaxis because of the fear of bleeding. Therefore, there is an urgent need for safer anticoagulants. Recent investigations into the biochemistry of hemostasis and thrombosis have identified new targets for development of novel anticoagulants...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28095402/a-general-shear-dependent-model-for-thrombus-formation
#6
Alireza Yazdani, He Li, Jay D Humphrey, George Em Karniadakis
Modeling the transport, activation, and adhesion of platelets is crucial in predicting thrombus formation and growth following a thrombotic event in normal or pathological conditions. We propose a shear-dependent platelet adhesive model based on the Morse potential that is calibrated by existing in vivo and in vitro experimental data and can be used over a wide range of flow shear rates ([Formula: see text]). We introduce an Eulerian-Lagrangian model where hemodynamics is solved on a fixed Eulerian grid, while platelets are tracked using a Lagrangian framework...
January 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28032527/bioreactivity-of-stent-material-activation-of-platelets-coagulation-leukocytes-and-endothelial-cell-dysfunction-in-vitro
#7
Veronique Ollivier, Caroline Roques, Nicolas Receveur, Matthias Gratz, Laurent Feldman, Didier Letourneur, Christian Gachet, Pierre H Mangin, Martine Jandrot-Perrus
Outcome of patients with coronary artery disease has been significantly improved by percutaneous coronary interventions with stent implantation. However, despite progress made on devices and antithrombotic treatments, stent thrombosis remains an important issue because of serious adverse consequences. Several mechanisms are assumed to favor stent thrombosis as platelet aggregation, fibrin formation, defective healing and local inflammation. The objective of this study was to evaluate in vitro the thrombogenicity, proinflammatory properties and healing capacities of cobalt-chromium (CoCr), an alloy commonly used for cardiovascular implants...
December 29, 2016: Platelets
https://www.readbyqxmd.com/read/28007958/polyphosphate-and-rna-differentially-modulate-the-contact-pathway-of-blood-clotting
#8
Joshua M Gajsiewicz, Stephanie A Smith, James H Morrissey
The contact pathway of the plasma clotting cascade is dispensable for normal hemostasis, but contributes to thrombosis and serves as a bridge between inflammation and coagulation. This pathway is triggered upon exposure of plasma to certain anionic polymers and artificial surfaces. Recently, extracellular nucleic acids and inorganic polyphosphate (polyP) have been implicated as being important (patho)physiologically relevant activators of this pathway. However, mechanistic details regarding how nucleic acids or polyP modulate the individual reactions of the contact pathway have been lacking...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27925683/inorganic-polyphosphate-a-key-modulator-of-inflammation
#9
REVIEW
S M Hassanian, A Avan, A Ardeshirylajimi
Inorganic polyphosphate (PolyP) is a molecule with prothrombotic and proinflammatory properties in blood. PolyP activates the NF-κB signaling pathway, increases the expression of cell surface adhesion molecules and disrupts the vascular barrier integrity of endothelial cells. PolyP-induced NF-κB activation and vascular hyperpermeability are regulated by the mammalian target of rapamycin complex-1 (mTORC1) and mTORC2 pathways, respectively. Through interaction with receptor for advanced glycation end products (RAGE) and P2Y1 receptors, PolyP dramatically amplifies the proinflammatory responses of nuclear proteins...
February 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27919911/in-vitro-activation-of-coagulation-by-human-neutrophil-dna-and-histone-proteins-but-not-neutrophil-extracellular-traps
#10
Denis F Noubouossie, Matthew F Whelihan, Yuan-Bin Yu, Erica Sparkenbaugh, Rafal Pawlinski, Dougald M Monroe, Nigel S Key
NETosis is a physiologic process in which neutrophils release their nuclear material in the form of neutrophil extracellular traps (NETs). NETs have been reported to directly promote thrombosis in animal models. Although the effects of purified NET components including DNA, histone proteins, and neutrophil enzymes on coagulation have been characterized, the mechanism by which intact NETs promote thrombosis is largely unknown. In this study, human neutrophils were stimulated to produce NETs in platelet-free plasma (PFP) or in buffer using phorbol myristate actetate or calcium ionophore...
February 23, 2017: Blood
https://www.readbyqxmd.com/read/27918944/groundwater-nitrate-pollution-and-human-health-risk-assessment-by-using-hhra-model-in-an-agricultural-area-ne-china
#11
Yuanzheng Zhai, Xiaobing Zhao, Yanguo Teng, Xiao Li, Junjun Zhang, Jin Wu, Rui Zuo
In order to learn the pollution circumstance of groundwater nitrate detailedly in Songnen Plain of Northeast China and estimate its potential risk to human health of local residents, a total of 389 groundwater samples were collected in 2014 and studied from residential areas and public water supply wells in 11 cities and counties in southeastern of Songnen Plain. The analysis results showed that the spatial distributions of main chemical components in groundwater had great variations with statistical concentrations in the order of TDS> HCO3> Ca> NO3> Cl> Na> SO4> Mg> K> NH4> NO2...
March 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/27848184/the-initiation-and-effects-of-plasma-contact-activation-an-overview
#12
REVIEW
Lisha Lin, Mingyi Wu, Jinhua Zhao
The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial...
March 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/27431334/effects-of-an-acidic-environment-on-coagulation-dynamics
#13
M Gissel, K E Brummel-Ziedins, S Butenas, A E Pusateri, K G Mann, T Orfeo
BACKGROUND: Disruption of hydrogen ion homeostasis is a consequence of traumatic injury often associated with clinical coagulopathy. Mechanisms by which acidification of the blood lead to aberrant coagulation require further elucidation. OBJECTIVE: To examine the effects of acidified conditions on coagulation dynamics using in vitro models of increasing complexity. METHODS: Coagulation dynamics were assessed at pH 7.4 and 7.0 as follows: 1) Tissue factor (TF)-initiated coagulation proteome mixtures (± factor (F)XI, ± fibrinogen/FXIII), with reaction progress monitored as thrombin generation or fibrin formation; 2) Enzyme/inhibitor reactions; 3) TF-dependent or -independent clot dynamics in contact pathway inhibited blood via viscoelastometry...
July 19, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27411493/environmental-exposure-to-cadmium-health-risk-assessment-and-its-associations-with-hypertension-and-impaired-kidney-function
#14
Haiyun Wu, Qilin Liao, Steven N Chillrud, Qiang Yang, Lei Huang, Jun Bi, Beizhan Yan
Cadmium (Cd) is a toxic metal. This study was aimed to estimate the potential health risks in a Cd-polluted district in China, and examine the relationship between urinary cadmium(UCd) and hypertension and impaired kidney function at low exposure levels (UCd: GM 1.3 μg/g creatinine). Blood pressure measurement, questionnaires, and collection of urinary samples were conducted from 217 residents. Environmental samples, food, and cigarette samples were collected and detected to estimate the risks posed by Cd and the contribution of inhalation, ingestion, and dermal contact pathways to these risks...
July 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27405511/artificial-dense-granules-a-procoagulant-liposomal-formulation-modeled-after-platelet-polyphosphate-storage-pools
#15
Alexander J Donovan, Joseph Kalkowski, Magdalena Szymusiak, Canhui Wang, Stephanie A Smith, Robert F Klie, James H Morrissey, Ying Liu
Granular platelet-sized polyphosphate nanoparticles (polyP NPs) were encapsulated in sterically stabilized liposomes, forming a potential, targeted procoagulant nanotherapy resembling human platelet dense granules in both structure and functionality. Dynamic light scattering (DLS) measurements reveal that artificial dense granules (ADGs) are colloidally stable and that the granular polyP NPs are encapsulated at high efficiencies. High-resolution scanning transmission electron microscopy (HR-STEM) indicates that the ADGs are monodisperse particles with a 150 nm diameter dense core consisting of P, Ca, and O surrounded by a corrugated 25 nm thick shell containing P, C, and O...
August 8, 2016: Biomacromolecules
https://www.readbyqxmd.com/read/27207433/the-hemostatic-role-of-factor-xi
#16
REVIEW
Cristina Puy, Rachel A Rigg, Owen J T McCarty
Coagulation factor (F)XI has been described as a component of the early phase of the contact pathway of blood coagulation, acting downstream of factor XII. However, patients deficient in upstream members of the contact pathway, including FXII and prekallikrein, do not exhibit bleeding complications, while FXI-deficient patients sometimes experience mild bleeding, suggesting FXI plays a role in hemostasis independent of the contact pathway. Further complicating the picture, bleeding risk in FXI-deficient patients is difficult to predict because bleeding symptoms have not been found to correlate with FXI antigen levels or activity...
May 2016: Thrombosis Research
https://www.readbyqxmd.com/read/26862185/caveats-in-studies-of-the-physiological-role-of-polyphosphates-in-coagulation
#17
REVIEW
Tomas L Lindahl, Sofia Ramström, Niklas Boknäs, Lars Faxälv
Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets...
February 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/26827162/synthesis-evaluation-and-structure-activity-relationship-of-new-3-carboxamide-coumarins-as-fxiia-inhibitors
#18
Charlotte Bouckaert, Silvia Serra, Grégoire Rondelet, Eduard Dolušić, Johan Wouters, Jean-Michel Dogné, Raphaël Frédérick, Lionel Pochet
Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile...
March 3, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26745503/in-vitro-mode-of-action-and-anti-thrombotic-activity-of-boophilin-a-multifunctional-kunitz-protease-inhibitor-from-the-midgut-of-a-tick-vector-of-babesiosis-rhipicephalus-microplus
#19
Teresa C Assumpção, Dongying Ma, Daniella M Mizurini, R Manjunatha Kini, José M C Ribeiro, Michail Kotsyfakis, Robson Q Monteiro, Ivo M B Francischetti
BACKGROUND: Hematophagous mosquitos and ticks avoid host hemostatic system through expression of enzyme inhibitors targeting proteolytic reactions of the coagulation and complement cascades. While most inhibitors characterized to date were found in the salivary glands, relatively few others have been identified in the midgut. Among those, Boophilin is a 2-Kunitz multifunctional inhibitor targeting thrombin, elastase, and kallikrein. However, the kinetics of Boophilin interaction with these enzymes, how it modulates platelet function, and whether it inhibits thrombosis in vivo have not been determined...
January 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/26670620/new-infestin-4-mutants-with-increased-selectivity-against-factor-xiia
#20
Vladimir N Kolyadko, Sofya V Lushchekina, Tatiana A Vuimo, Stepan S Surov, Ruzanna A Ovsepyan, Vera A Korneeva, Ivan I Vorobiev, Nadezhda A Orlova, Leonid Minakhin, Konstantin Kuznedelov, Konstantin V Severinov, Fazoil I Ataullakhanov, Mikhail A Panteleev
Factor XIIa (fXIIa) is a serine protease that triggers the coagulation contact pathway and plays a role in thrombosis. Because it interferes with coagulation testing, the need to inhibit fXIIa exists in many cases. Infestin-4 (Inf4) is a Kazal-type inhibitor of fXIIa. Its specificity for fXIIa can be enhanced by point mutations in the protease-binding loop. We attempted to adapt Inf4 for the selective repression of the contact pathway under various in vitro conditions, e.g., during blood collection and in 'global' assays of tissue factor (TF)-dependent coagulation...
2015: PloS One
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