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Activated factor xiia

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https://www.readbyqxmd.com/read/29784539/revisiting-antithrombin-in-health-and-disease-congenital-deficiencies-and-genetic-variants-and-laboratory-studies-on-%C3%AE-and-%C3%AE-forms
#1
REVIEW
Jean Amiral, Jerard Seghatchian
Antithrombin [AT] is the main inhibitor for activated plasma coagulation serine esterases, inhibiting thrombin, Factors Xa and IXa, but also Factors XIIa, XIa, VIIa, kallicrein, and plasmin. Its activity is highly enhanced by heparin, through binding to the pentasaccharide sequences, for inhibition of all coagulation proteases, except thrombin, which inhibition requires its additional binding to the heparin polysaccharide chain. However, AT is the major inhibitor of thrombin in the blood circulation. Congenital or acquired deficiencies of AT expose affected patients to an increased risk of developing unprovoked and recurrent thrombo-embolic diseases...
April 19, 2018: Transfusion and Apheresis Science
https://www.readbyqxmd.com/read/29724819/establishing-the-transient-mass-balance-of-thrombosis-from-tissue-factor-to-thrombin-to-fibrin-under-venous-flow
#2
Shu Zhu, Jason Chen, Scott L Diamond
OBJECTIVE: We investigated the coregulation of thrombin and fibrin as blood flows over a procoagulant surface. APPROACH AND RESULTS: Using microfluidic perfusion of factor XIIa-inhibited human whole blood (200 s- 1 wall shear rate) over a 250-μ long patch of collagen/TF (tissue factor; ≈1 molecule per μm2 ) and immunoassays of the effluent for F1.2 (prothrombin fragment 1.2), TAT (thrombin-antithrombin complex), and D-dimer (post-end point plasmin digest), we sought to establish the transient mass balance for clotting under venous flow...
May 3, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29519898/structures-of-human-plasma-%C3%AE-factor-xiia-cocrystallized-with-potent-inhibitors
#3
Alexey Dementiev, Abel Silva, Calvin Yee, Zhe Li, Michael T Flavin, Hing Sham, James R Partridge
Activated factor XIIa (FXIIa) is a serine protease that has received a great deal of interest in recent years as a potential target for the development of new antithrombotics. Despite the strong interest in obtaining structural information, only the structure of the FXIIa catalytic domain in its zymogen conformation is available. In this work, reproducible experimental conditions found for the crystallization of human plasma β-FXIIa and crystal growth optimization have led to determination of the first structure of the active form of the enzyme...
March 13, 2018: Blood Advances
https://www.readbyqxmd.com/read/29437288/staphylococcus-aureus-induced-complement-activation-promotes-tissue-factor-mediated-coagulation
#4
E W Skjeflo, D Christiansen, H Fure, J K Ludviksen, T M Woodruff, T Espevik, E W Nielsen, O L Brekke, T E Mollnes
Essentials Complement, Toll-like receptors and coagulation cross-talk in the process of thromboinflammation. This is explored in a unique human whole-blood model of S. aureus bacteremia. Coagulation is here shown as a downstream event of C5a-induced tissue factor (TF) production. Combined inhibition of C5 and CD14 efficiently attenuated TF and coagulation. SUMMARY: Background There is extensive cross-talk between the complement system, the Toll-like receptors (TLRs), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor (TF) expression...
May 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29378358/chemical-footprinting-reveals-conformational-changes-following-activation-of-factor-xi
#5
Ingrid Stroo, J Arnoud Marquart, Kamran Bakhtiari, Tom Plug, Alexander B Meijer, Joost C M Meijers
Coagulation factor XI is activated by thrombin or factor XIIa resulting in a conformational change that converts the catalytic domain into its active form and exposing exosites for factor IX on the apple domains. Although crystal structures of the zymogen factor XI and the catalytic domain of the protease are available, the structure of the apple domains and hence the interactions with the catalytic domain in factor XIa are unknown. We now used chemical footprinting to identify lysine residue containing regions that undergo a conformational change following activation of factor XI...
February 2018: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29354798/activity-of-factor-xii-locarno
#6
Bassem M Mohammed, Ivan Ivanov, Anton Matafonov, Jonas Emsley, David Gailani
Background: Factor XII (FXII) Locarno is a natural variant with proline replacing Arg353 at the activation cleavage site, preventing conversion to the fully active protease factor XIIa (FXIIa). Recently, we showed that FXII restricted to a single chain form (sc-FXII) by replacing Arg353 with alanine expresses proteolytic activity that is enhanced by cofactors such as polyphosphate. Aim: To determine if the Pro353 substitution affects the activity of sc-FXII. Methods: Wild type FXII (FXII-WT), FXII-R353A, and FXII Locarno (FXII-R353P) were tested for their abilities to activate prekallikrein, and to induce thrombin generation and coagulation in plasma in a factor XI-dependent manner...
January 2018: Research and Practice in Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28941135/hemocompatibility-of-ca-2-crosslinked-nanocellulose-hydrogels-toward-efficient-management-of-hemostasis
#7
Alex Basu, Jaan Hong, Natalia Ferraz
The present work investigates Ca(2+) -crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing-the blood. Hydrogels of wood-derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet-free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation...
November 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28918098/identifying-novel-factor-xiia-inhibitors-with-pca-ga-svm-developed-vhts-models
#8
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...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28816340/coagulation-factor-xii-regulates-inflammatory-responses-in-human-lungs
#9
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...
October 5, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28804827/assessment-of-hereditary-thrombophilia-performance-of-antithrombin-at-testing
#10
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
#11
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
#12
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
#13
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...
September 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
#14
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 Ca2+ -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 Ca2+ /Mg2+ 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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