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Activated factor xiia

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https://www.readbyqxmd.com/read/28918098/identifying-novel-factor-xiia-inhibitors-with-pca-ga-svm-developed-vhts-models
#1
Jonathan Jun Feng Chen, Donald P Visco
There currently is renewed interest in blood clotting Factor XII as a potential target for thrombosis inhibition. Historically untargeted, there is little drug information with which to start drug candidate searches. Typical high-throughput screening can identify potential drug candidates, but is inefficient. Virtual high-throughput screening can be used to raise efficiency by focusing experimental efforts on compounds predicted to be active and is applied here to identify new Factor XIIa inhibitors. We combine principal component analysis, genetic algorithm and support vector machine to create the models used in the virtual high-throughput screening...
September 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28816340/coagulation-factor-xii-regulates-inflammatory-responses-in-human-lungs
#2
Rosanna Hess, Lukasz Wujak, Christina Hesse, Katherina Sewald, Danny Jonigk, Gregor Warnecke, Hans-Gerd Fieguth, Steven de Maat, Coen Maas, Francesco Bonella, Klaus T Preissner, Benjamin Weiss, Liliana Schaefer, Wolfgang M Kuebler, Philipp Markart, Malgorzata Wygrecka
Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array...
August 17, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28804827/assessment-of-hereditary-thrombophilia-performance-of-antithrombin-at-testing
#3
Jana N Gausman, Richard A Marlar
Antithrombin (AT) is a naturally occurring plasma inhibitor of coagulation, which is a synthesized in the liver. AT inhibits coagulation serine proteases (the enzymatically activated forms of the clotting factors), mainly thrombin (factor IIa) and factor Xa, but also to a lesser extent factors IXa, XIa, and XIIa. Acting alone, AT inhibits coagulation factors, but does this very slowly; however, when coupled with heparin as a cofactor, the speed of inhibition is increased many fold. The AT/Heparin complex is the most powerful naturally occurring anticoagulant in blood...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28738274/discovery-and-assessment-of-water-soluble-coumarins-as-inhibitors-of-the-coagulation-contact-pathway
#4
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/28726978/analysis-of-the-substrate-specificity-of-factor-vii-activating-protease-fsap-and-design-of-specific-and-sensitive-peptide-substrates
#5
Emrah Kara, Dipankar Manna, Geir Åge Løset, Eric L Schneider, Charles S Craik, Sandip Kanse
Factor VII (FVII) activating protease (FSAP) is a circulating serine protease that is likely to be involved in a number of disease conditions such as stroke, atherosclerosis, liver fibrosis, thrombosis and cancer. To date, no systematic information is available about the substrate specificity of FSAP. Applying phage display and positional scanning substrate combinatorial library (PS-SCL) approaches we have characterised the specificity of FSAP towards small peptides. Results were evaluated in the context of known protein substrates as well as molecular modelling of the peptides in the active site of FSAP...
August 30, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28632925/a-kallikrein-targeting-rna-aptamer-inhibits-the-intrinsic-pathway-of-coagulation-and-reduces-bradykinin-release
#6
K-A Steen Burrell, J Layzer, B A Sullenger
Essentials Kallikrein amplifies contact activation and is a potential target for preventing thrombosis. We developed and characterized a kallikrein aptamer using convergent evolution and kinetic assays. Kall1-T4 prolongs intrinsic clotting time by inhibiting factor XIIa-mediated prekallikrein activation. Kall1-T4 decreases high-molecular-weight kininogen cleavage and bradykinin release. SUMMARY: Background Plasma kallikrein is a serine protease that plays an integral role in many biological processes, including coagulation, inflammation, and fibrinolysis...
June 20, 2017: Journal of Thrombosis and Haemostasis: JTH
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
#7
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/28219400/alleviation-of-secondary-brain-injury-posttraumatic-inflammation-and-brain-edema-formation-by-inhibition-of-factor-xiia
#8
Sarah Hopp, Marc W Nolte, Christian Stetter, Christoph Kleinschnitz, Anna-Leena Sirén, Christiane Albert-Weissenberger
BACKGROUND: Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI...
February 20, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28137735/contact-system-activation-and-high-thrombin-generation-in-hyperthyroidism
#9
Namhee Kim, Ja-Yoon Gu, Hyun Ju Yoo, Se Eun Han, Young Il Kim, Il Sung Nam-Goong, Eun Sook Kim, Hyun Kyung Kim
BACKGROUND: Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extracellular traps (NET) has emerged as an important trigger of thrombosis, we hypothesized that the contact system is activated along with active NET formation in hyperthyroidism and that their markers correlate with disease severity. SUBJECTS AND METHODS: In 61 patients with hyperthyroidism and 40 normal controls, the levels of coagulation factors (fibrinogen, and factor VII, VIII, IX, XI and XII), D-dimer, thrombin generation assay (TGA) markers, NET formation markers (histone-DNA complex, double-stranded DNA and neutrophil elastase) and contact system markers (activated factor XII (XIIa), high-molecular-weight kininogen (HMWK), prekallikrein and bradykinin) were measured...
May 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28124063/nucleic-acids-as-cofactors-for-factor-xi-and-prekallikrein-activation-different-roles-for-high-molecular-weight-kininogen
#10
Ivan Ivanov, Ruhama Shakhawat, Mao-Fu Sun, S Kent Dickeson, Cristina Puy, Owen J T McCarty, Andras Gruber, Anton Matafonov, David Gailani
The plasma zymogens factor XI (fXI) and prekallikrein (PK) are activated by factor XIIa (fXIIa) during contact activation. Polyanions such as DNA and RNA may contribute to thrombosis and inflammation partly by enhancing PK and fXI activation. We examined PK and fXI activation in the presence of nucleic acids, and determine the effects of the cofactor high molecular weight kininogen (HK) on the reactions. In the absence of HK, DNA and RNA induced fXI autoactivation. Proteases known to activate fXI (fXIIa and thrombin) did not enhance this process appreciably...
April 3, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28035006/factor-xiia-as-a-novel-target-for-thrombosis-target-engagement-requirement-and-efficacy-in-a-rabbit-model-of-microembolic-signals
#11
Christopher M Barbieri, Xinkang Wang, Weizhen Wu, Xueping Zhou, Aimie M Ogawa, Kim O'Neill, Donald Chu, Gino Castriota, Dietmar A Seiffert, David E Gutstein, Zhu Chen
Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa that is needed for efficacy and the impact of FXIIa inhibition on cerebral embolism. A selective activated FXII (FXIIa) inhibitor, recombinant human albumin-tagged mutant Infestin-4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin-4 (human FXIIa inhibition constant = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against Factor Xa (FXa) and plasmin...
March 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28007958/polyphosphate-and-rna-differentially-modulate-the-contact-pathway-of-blood-clotting
#12
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/27791187/serum-stimulation-of-ccr7-chemotaxis-due-to-coagulation-factor-xiia-dependent-production-of-high-molecular-weight-kininogen-domain-5
#13
Manish P Ponda, Jan L Breslow
Chemokines and their receptors play a critical role in immune function by directing cell-specific movement. C-C chemokine receptor 7 (CCR7) facilitates entry of T cells into lymph nodes. CCR7-dependent chemotaxis requires either of the cognate ligands C-C chemokine ligand 19 (CCL19) or CCL21. Although CCR7-dependent chemotaxis can be augmented through receptor up-regulation or by increased chemokine concentrations, we found that chemotaxis is also markedly enhanced by serum in vitro. Upon purification, the serum cofactor activity was ascribed to domain 5 of high-molecular-weight kininogen...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27783665/regulation-of-complement-and-contact-system-activation-via-c1-inhibitor-potentiation-and-factor-xiia-activity-modulation-by-sulfated-glycans-structure-activity-relationships
#14
Ann-Kathrin Schoenfeld, Eric Lahrsen, Susanne Alban
The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH...
2016: PloS One
https://www.readbyqxmd.com/read/27273087/complement-kinins-and-hereditary-angioedema-mechanisms-of-plasma-instability-when-c1-inhibitor-is-absent
#15
REVIEW
Allen P Kaplan, Kusumam Joseph
Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4...
October 2016: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/27246526/angioedema-attacks-in-patients-with-hereditary-angioedema-local-manifestations-of-a-systemic-activation-process
#16
REVIEW
Zonne L M Hofman, Anurag Relan, Sacha Zeerleder, Christian Drouet, Bruce Zuraw, C Erik Hack
Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack...
August 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27200353/a-cross-sectional-study-of-klkb1-and-prcp-polymorphisms-in-patient-samples-with-cardiovascular-disease
#17
Haley R Gittleman, Alona Merkulova, Omar Alhalabi, Evi X Stavrou, Martina L Veigl, Jill S Barnholtz-Sloan, Alvin H Schmaier
Plasma kallikrein formed from prekallikrein (PK) produces bradykinin from kininogens and activates factor XII. Plasma PK is activated by factors αXIIa, βXIIa, or prolylcarboxypeptidase (PRCP). A cross-sectional investigation determined if there is an association of PRCP and KLKB1 polymorphisms with cardiovascular disease (CVD). DNA was obtained from 2243 individuals from the Prevention of Events with Angiotensin Converting Enzyme trial. Two PRCP SNPs, rs7104980 and rs2298668, and two KLKB1 SNPs, rs3733402 and rs3087505, were genotyped...
2016: Frontiers in Medicine
https://www.readbyqxmd.com/read/27126647/animal-models-of-thrombosis-from-zebrafish-to-nonhuman-primates-use-in-the-elucidation-of-new-pathologic-pathways-and-the-development-of-antithrombotic-drugs
#18
REVIEW
Pudur Jagadeeswaran, Brian C Cooley, Peter L Gross, Nigel Mackman
Thrombosis is a leading cause of morbidity and mortality worldwide. Animal models are used to understand the pathological pathways involved in thrombosis and to test the efficacy and safety of new antithrombotic drugs. In this review, we will first describe the central role a variety of animal models of thrombosis and hemostasis has played in the development of new antiplatelet and anticoagulant drugs. These include the widely used P2Y12 antagonists and the recently developed orally available anticoagulants that directly target factor Xa or thrombin...
April 29, 2016: Circulation Research
https://www.readbyqxmd.com/read/27058272/evidence-of-contact-activation-in-patients-suffering-from-st-elevation-myocardial-infarction
#19
Kjeld Christensen, Huda Kozarcanin, Kristina N Ekdahl, Bo Nilsson
INTRODUCTION: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. METHODS AND PATIENTS: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3days post-percutaneous intervention (PCI) and, in one-third of the patients, 3months after PCI...
May 2016: Thrombosis Research
https://www.readbyqxmd.com/read/27018196/hereditary-and-acquired-c1-inhibitor-dependent-angioedema-from-pathophysiology-to-treatment
#20
REVIEW
Sacha Zeerleder, Marcel Levi
Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation...
2016: Annals of Medicine
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