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https://www.readbyqxmd.com/read/27924212/combined-administration-of-the-gpvi-fc-fusion-protein-revacept-with-low-dose-thrombolysis-in-the-treatment-of-stroke
#1
Andreas Reimann, Zhongmin Li, Silvia Goebel, Julia Fassbender, Hans-Peter Holthoff, Meinrad Gawaz, Götz Münch, Martin Ungerer
BACKGROUND: Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) remains the only approved medication for acute ischemic stroke, but incurs significant bleeding risks. Therefore, approaches to combine lower doses of thrombolytic therapy with other effective drugs aim at improving efficacy and reducing bleeding rates. We examined the safety and therapeutic effects of various dosings of rtPA, either alone or combined with glycoprotein VI-Fc fusion protein (GPVI-Fc, Revacept) on experimental stroke in mice...
January 2016: Heart International
https://www.readbyqxmd.com/read/27896950/ppar%C3%AE-agonists-negatively-regulate-%C3%AE-iib%C3%AE-3-integrin-outside-in-signalling-and-platelet-function-through-upregulation-of-protein-kinase-a-activity
#2
A J Unsworth, N Kriek, A P Bye, K Naran, T Sage, G D Flora, J M Gibbins
BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis...
November 29, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27818280/gpvi-and-thromboxane-receptor-on-platelets-promote-proinflammatory-macrophage-phenotypes-during-cutaneous-inflammation
#3
Sandra Pierre, Bona Linke, Suo Jing, Neda Tarighi, Domenico Del Turco, Dominique Thomas, Nerea Ferreiros, David Stegner, Stefanie Frölich, Marco Sisignano, Sascha Meyer Dos Santos, Natasja deBruin, Rolf M Nüsing, Thomas Deller, Bernhard Nieswandt, Gerd Geisslinger, Klaus Scholich
Platelets are well known for their role in hemostasis but are also increasingly recognized for their supporting role in innate immune responses. Here, we studied the role of platelets in the development of peripheral inflammation and found that platelets colocalize with macrophages in the inflamed tissue outside of blood vessels in different animal models for cutaneous inflammation. In macrophages isolated from paws during zymosan-induced inflammation treatment with collagen-induced thromboxane synthesis through the platelet-expressed collagen receptor glycoprotein VI (GPVI)...
November 3, 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27778530/gpvi-modulation-during-platelet-activation-and-storage-its-expression-levels-and-ectodomain-shedding-compared-to-markers-of-platelet-storage-lesion
#4
Ehteramolsadat Hosseini, Mehran Ghasemzadeh, Fatemeh Nassaji, Zeynab Pirmohammad Jamaat
Platelet storage is associated with deleterious changes leading to the loss of platelet reactivity and response. During storage, platelets experience increased expression and shedding of P-selectin and CD40L as specific markers of platelet activation, whereas GPIbα decreases due to ectodomain shedding. As an important adhesive receptor, GPVI contributes significantly to thrombus formation while its expression and shedding levels during storage of platelet products have not been well characterized yet. This study investigated the modulation of GPVI during platelet storage...
October 25, 2016: Platelets
https://www.readbyqxmd.com/read/27766315/cross-linking-gpvi-fc-by-anti-fc-antibodies-potentiates-its-inhibition-of%C3%A2-atherosclerotic-plaque-and-collagen-induced-platelet-activation
#5
Janina Jamasbi, Remco T A Megens, Mariaelvy Bianchini, Kerstin Uhland, Götz Münch, Martin Ungerer, Shachar Sherman, Alexander Faussner, Richard Brandl, Christine John, Johannes Buchner, Christian Weber, Reinhard Lorenz, Natalie Elia, Wolfgang Siess
To enhance the antithrombotic properties of recombinant glycoprotein VI fragment crystallizable (GPVI-Fc), the authors incubated GPVI-Fc with anti-human Fc antibodies to cross-link the Fc tails of GPVI-Fc. Cross-linking potentiated the inhibition of human plaque- and collagen-induced platelet aggregation by GPVI-Fc under static and flow conditions without increasing bleeding time in vitro. Cross-linking with anti-human-Fc Fab2 was even superior to anti-human-Fc immunoglobulin G (IgG). Advanced optical imaging revealed a continuous sheath-like coverage of collagen fibers by cross-linked GPVI-Fc complexes...
April 2016: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/27766055/platelets-and-platelet-adhesion-molecules-novel-mechanisms-of-thrombosis-and-anti-thrombotic-therapies
#6
REVIEW
Xiaohong Ruby Xu, Naadiya Carrim, Miguel Antonio Dias Neves, Thomas McKeown, Tyler W Stratton, Rodrigo Matos Pinto Coelho, Xi Lei, Pingguo Chen, Jianhua Xu, Xiangrong Dai, Benjamin Xiaoyi Li, Heyu Ni
Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that occurs prior to platelet accumulation (i...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27766044/anti-thrombotic-agents-derived-from-snake-venom-proteins
#7
Tur-Fu Huang, Chun-Chieh Hsu, Yu-Ju Kuo
Snake venoms affect blood coagulation and platelet function in a complex manner. However, two classes of venom proteins, snaclecs and disintegrins have been shown to specifically target receptors including GPIb, α2β1, GPVI, CLEC-2 and integrins αIIbβ3, αvβ3, α5β1 expressed on platelets, endothelial cells, phagocytes, tumor cells, thus affecting cell-matrices and cell-cell interactions. Here, we focus on disintegrins, a class of low molecular mass Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing, cysteine-rich polypeptide derived from various viper snake venoms...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27761580/decreased-platelet-reactivity-in-patients-with-cancer-is-associated-with-high-risk-of-venous-thromboembolism-and-poor-prognosis
#8
Julia Riedl, Alexandra Kaider, Christine Marosi, Gerald W Prager, Beate Eichelberger, Alice Assinger, Ingrid Pabinger, Simon Panzer, Cihan Ay
Platelets are suggested to play a crucial role in cancer progression and the prothrombotic state of cancer patients. Here, we aimed to examine the activation status of platelets in cancer patients and investigate their association with risk of death and occurrence of venous thromboembolism (VTE) in a prospective observational cohort study. We measured platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation in vivo and platelet response to ex vivo stimulation with agonists of protease-activated receptor (PAR) -1, -4, and GPVI, by whole blood flow cytometry, before beginning of chemotherapy and repeatedly during the first six months thereafter (total number of samples analysed: 230)...
October 20, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27753514/clinical-significance-of-receptor-shedding-platelet-gpvi-as-an-emerging-diagnostic-and-therapeutic-tool
#9
Madhumita Chatterjee, Meinrad Gawaz
Platelet membrane bedecked with a wide array of receptors offers a platform to regulate platelet responsiveness, thrombotic propensity, inflammatory disposition, and immune reactivity under diverse pathophysiological conditions. Ectopic proteolytic cleavage of such receptors irreversibly inactivates receptor-mediated intracellular signaling governing cellular functions, further releases soluble fragments into circulation which might modulate functions of target cells. Glycoprotein VI-(GPVI) is a membrane glycoprotein expressed in platelets and megakaryocytes...
October 18, 2016: Platelets
https://www.readbyqxmd.com/read/27716777/thioredoxin-inhibitors-attenuate-platelet-function-and-thrombus-formation
#10
Clive Metcalfe, Anjana Ramasubramoni, Giordano Pula, Matthew T Harper, Stuart J Mundell, Carmen H Coxon
Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis...
2016: PloS One
https://www.readbyqxmd.com/read/27693274/anti-xa-oral-anticoagulants-inhibit-in-vivo-platelet-activation-by-modulating-glycoprotein-vi-shedding
#11
Pasquale Pignatelli, Daniele Pastori, Simona Bartimoccia, Danilo Menichelli, Tommasa Vicario, Cristina Nocella, Roberto Carnevale, Francesco Violi
Anti Xa non-vitamin K oral anticoagulants (anti Xa NOACs) seem to possess antiplatelet effect in vitro, but it is unclear if this occurs also in vivo. Aim of the study was to compare the effect on platelet activation of two anti Xa NOACs, namely apixaban and rivaroxaban, to warfarin, and to investigate the potential underlying mechanism by evaluating soluble glycoprotein GPVI (sGPVI), a protein involved in platelet activation. We performed a cross-sectional including AF patients treated with warfarin (n=30), or apixaban 10mg/day (n=40), or rivaroxaban 20mg/day (n=40)...
September 28, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27687726/psoralen-and-ultraviolet-a-light-treatment-directly-affects-phosphatidylinositol-3-kinase-signal-transduction-by-altering-plasma-membrane-packing
#12
Britt Van Aelst, Rosalie Devloo, Pierre Zachée, Ruben t'Kindt, Koen Sandra, Philippe Vandekerckhove, Veerle Compernolle, Hendrik B Feys
Psoralen and ultraviolet A light (PUVA) are used to kill pathogens in blood products and as a treatment of aberrant cell proliferation in dermatitis, cutaneous T-cell lymphoma, and graft-versus-host disease. DNA damage is well described, but the direct effects of PUVA on cell signal transduction are poorly understood. Because platelets are anucleate and contain archetypal signal transduction machinery, they are ideally suited to address this. Lipidomics on platelet membrane extracts showed that psoralen forms adducts with unsaturated carbon bonds of fatty acyls in all major phospholipid classes after PUVA...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27609517/tula-2-protein-phosphatase-suppresses-activation-of-syk-through-the-gpvi-platelet-receptor-for-collagen-by-dephosphorylating-tyr-p-346-a-regulatory-site-of-syk
#13
Kevin Reppschläger, Jeanne Gosselin, Carol A Dangelmaier, Dafydd H Thomas, Nick Carpino, Steven E McKenzie, Satya P Kunapuli, Alexander Y Tsygankov
Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets...
October 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27601054/mechanical-circulatory-support-is-associated-with-loss-of-platelet-receptors-glycoprotein-ib%C3%AE-and-glycoprotein-vi
#14
P Lukito, A Wong, J Jing, J F Arthur, S F Marasco, D A Murphy, P J Bergin, J A Shaw, M Collecutt, R K Andrews, E E Gardiner, A K Davis
: Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use...
September 7, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27516430/liver-mediated-shedding-of-platelet-gpvi
#15
Michael C Berndt, Robert K Andrews
No abstract text is available yet for this article.
August 11, 2016: Blood
https://www.readbyqxmd.com/read/27505889/proplatelet-formation-is-selectively-inhibited-by-collagen-type-i-through-syk-independent-gpvi-signaling
#16
Daniela Semeniak, Rebecca Kulawig, David Stegner, Imke Meyer, Silke Schwiebert, Hendrik Bösing, Beate Eckes, Bernhard Nieswandt, Harald Schulze
Collagen receptors GPVI (also known as GP6) and integrin α2β1 are highly expressed on blood platelets and megakaryocytes, their immediate precursors. After vessel injury, subendothelial collagen becomes exposed and induces platelet activation to prevent blood loss. Collagen types I and IV are thought to have opposite effects on platelet biogenesis, directing proplatelet formation (PPF) towards the blood vessels to prevent premature release within the marrow cavity. We used megakaryocytes lacking collagen receptors or treated megakaryocytes with blocking antibodies, and could demonstrate that collagen-I-mediated inhibition of PPF is specifically controlled by GPVI...
September 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27494300/regulation-of-platelet-membrane-protein-shedding-in-health-and-disease
#17
Amanda E Au, Emma C Josefsson
Extracellular proteolysis of platelet plasma membrane proteins is an event that ensues platelet activation. Shedding of surface receptors such as glycoprotein (GP) Ibα, GPV and GPVI as well as externalized proteins P-selectin and CD40L releases soluble ectodomain fragments that are subsequently detectable in plasma. This results in the irreversible functional downregulation of platelet receptor-mediated adhesive interactions and the generation of biologically active fragments. In this review, we describe molecular insights into the regulation of platelet receptor and ligand shedding in health and disease...
August 5, 2016: Platelets
https://www.readbyqxmd.com/read/27480079/anti-platelet-and-anti-thrombogenic-effects-of-shikimic-acid-in-sedentary-population
#18
Daniel Veach, Holly Hosking, Kiara Thompson, Abishek Bommannan Santhakumar
This ex vivo study was performed to evaluate the anti-platelet and anti-thrombogenic potential of shikimic acid (SA), a plant phenolic metabolite. Fasting blood samples were collected from 22 sedentary participants to analyse the effect of varying concentrations of SA (0.1 mM, 0.2 mM, 0.5 mM, 1 mM and 2 mM) on platelet surface-marker expression, platelet aggregation and biomarkers of thrombogenesis. Monocyte-platelet aggregates (CD14/CD42b) and platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31), effective indicators of thrombus formation were evaluated...
August 10, 2016: Food & Function
https://www.readbyqxmd.com/read/27416950/increased-soluble-gpvi-levels-in-cirrhosis-evidence-for-early-in-vivo-platelet-activation
#19
Karl Egan, Audrey Dillon, Eimear Dunne, Barry Kevane, Zita Galvin, Patricia Maguire, Dermot Kenny, Stephen Stewart, Fionnuala Ni Ainle
Cirrhosis is a consequence of prolonged liver injury and is characterised by extensive tissue fibrosis: the deposition of collagen-rich extracellular matrix. The haemostatic balance is disordered in cirrhosis and coagulation activation appears to promote fibrosis. In spite of recent studies demonstrating a role for anticoagulant therapy in preventing cirrhosis progression, there has not been a change in clinical practice, suggesting that physicians are reluctant to anticoagulate patients with cirrhosis due to bleeding risks...
July 14, 2016: Journal of Thrombosis and Thrombolysis
https://www.readbyqxmd.com/read/27412718/novel-pharmacological-inhibitors-demonstrate-the-role-of-the-tyrosine-kinase-pyk2-in-adhesion-and-aggregation-of-human-platelets
#20
Gianni Francesco Guidetti, Marta Zarà, Ilaria Canobbio, Caterina Visconte, Giada Di Nunzio, Mauro Torti
Pyk2 is a Ca2+-regulated kinase predominantly expressed in neuronal and in haematopoietic cells. Previous studies on Pyk2-null mice have demonstrated that Pyk2 plays a crucial role in platelet activation and thrombus formation, thus representing a possible target for antithrombotic therapy. Very limited information is available about the role of Pyk2 in human platelets, mainly because of the lack of specific pharmacological inhibitors. In this work, we have tested two novel Pyk2 inhibitors, PF-4594755 and PF-4520440, to validate their specificity and to investigate their ability to modulate platelet activation...
July 14, 2016: Thrombosis and Haemostasis
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