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https://www.readbyqxmd.com/read/28981200/soluble-fibrin-causes-an-acquired-platelet-glycoprotein-vi-signaling-defect-implications-for-coagulopathy
#1
Mei Yan Lee, Christopher C Verni, Bradley A Herbig, Scott L Diamond
BACKGROUND: In coagulopathic blood, circulating thrombin may drive platelet dysfunction. METHODS/RESULTS: Using calcium dye-loaded platelets, the effect of thrombin exposure and soluble fibrin generation on subsequent platelet GPVI function was investigated. Exposure of apixaban-treated platelet-rich plasma (12% PRP) to thrombin (1-10 nM), but not ADP or thromboxane mimetic U46619 exposure, dramatically blocked subsequent GPVI activation by convulxin, collagen-related peptide, or fibrillar collagen...
October 5, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28960117/the-effects-of-signal-transducer-and-activator-of-transcription-three-mutations-on-human-platelets
#2
Floor E Aleva, Frank L van de Veerdonk, Yang Li, Rahajeng N Tunjungputri, Sami Simons, Philip G De Groot, Mihai M Netea, Yvonne F Heijdra, Quirijn de Mast, André J A M van der Ven
Involvement of signal transducer and activator of transcription 3 (STAT3) in inflammation is well known. Recently, a role for STAT3 in platelet activation and platelet production has been suggested. Platelets exhibit important immune functions and engagement of STAT3 in platelet physiology may link inflammation and hemostasis. This study investigated the effects of STAT3 loss-of-function mutations and single nucleotide polymorphisms (SNPs) in STAT3 on glycoprotein VI (GPVI)-mediated platelet activation and platelet numbers in humans...
September 29, 2017: Platelets
https://www.readbyqxmd.com/read/28953486/association-of-oxidative-stress-and-platelet-receptor-glycoprotein-gpib%C3%AE-and-gpvi-shedding-during-nonsurgical-bleeding-in-heart-failure-patients-with-continuous-flow-left-ventricular-assist-device-support
#3
Nandan K Mondal, Zengsheng Chen, Jaimin R Trivedi, Erik N Sorensen, Si M Pham, Mark S Slaughter, Bartley P Griffith, Zhongjun J Wu
Nonsurgical bleeding (NSB) in heart failure (HF) patients with continuous-flow left ventricular assist device (CF-LVAD) support is the most common clinical complication. The aim of this study was to investigate the association between oxidative stress and platelet glycoproteins GPIbα and GPVI shedding on the incidence of NSB in CF-LVAD patients. Fifty-one HF patients undergoing CF-LVAD implantation and 11 healthy volunteers were recruited. Fourteen patients developed NSB (bleeder group) during 1 month follow-up duration, while others were considered nonbleeder group (n = 37)...
September 26, 2017: ASAIO Journal: a Peer-reviewed Journal of the American Society for Artificial Internal Organs
https://www.readbyqxmd.com/read/28950757/better-platelet-function-less-fibrinolysis-and-less-hemolysis-in-re-transfused-residual-pump-blood-with-the-ringer-s-chase-technique-a-randomized-pilot-study
#4
Anki Olsson, Joakim Alfredsson, Sofia Ramström, Rolf Svedjeholm, Dermot Kenny, Eric Håkansson, Johan Sanmartin Berglund, Sören Berg
INTRODUCTION: Residual pump blood from the cardiopulmonary bypass (CPB) circuit is often collected into an infusion bag (IB) and re-transfused. An alternative is to chase the residual blood into the circulation through the arterial cannula with Ringer's acetate. Our aim was to assess possible differences in hemostatic blood quality between these two techniques. METHODS: Forty adult patients undergoing elective coronary artery bypass graft surgery with CPB were randomized to receive the residual pump blood by either an IB or through the Ringer's chase (RC) technique...
September 1, 2017: Perfusion
https://www.readbyqxmd.com/read/28944903/gpvi%C3%A2-fc%C3%A2-peg-improves-cerebral-infarct-volume-and-cerebral-thrombosis-in-mouse-model-with-cerebral-thrombosis
#5
Yimae Wufuer, Xuefeng Shan, Magaoweiya Sailike, Kamile Adilaimu, Songfeng Ma, Huguo Wang
Cerebral thrombosis is one of the most common causes of cerebral infarction, and anticoagulation therapy is a routine treatment in patients with hemorrhagic cerebral venous thrombosis. The hemostatic function of platelets is important for the anticoagulation therapy of thrombosis. Glycoprotein VI (GPVI) is reported as the major signaling receptor for collagen and is exclusively expressed on platelets and megakaryocytes, initiating platelet recruitment at sites of vascular injury and demonstrating numerous beneficial effects for patients with cerebral thrombosis...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28888895/regulation-of-platelet-activation-and-thrombus-formation-by-reactive-oxygen-species
#6
Jianlin Qiao, Jane F Arthur, Elizabeth E Gardiner, Robert K Andrews, Lingyu Zeng, Kailin Xu
Reactive oxygen species (ROS) are generated within activated platelets and play an important role in regulating platelet responses to collagen and collagen-mediated thrombus formation. As a major collagen receptor, platelet-specific glycoprotein (GP)VI is a member of the immunoglobulin (Ig) superfamily, with two extracellular Ig domains, a mucin domain, a transmembrane domain and a cytoplasmic tail. GPVI forms a functional complex with the Fc receptor γ-chain (FcRγ) that, following receptor dimerization, signals via an intracellular immunoreceptor tyrosine-based activation motif (ITAM), leading to rapid activation of Src family kinase signaling pathways...
September 7, 2017: Redox Biology
https://www.readbyqxmd.com/read/28878675/inhibition-of-collagen-induced-platelet-aggregation-by-the-secobutanolide-secolincomolide-a-from-lindera-obtusiloba-blume
#7
Sang-Hyuk Jung, Joo-Hui Han, Hyun-Soo Park, Jung-Jin Lee, Seo Young Yang, Young Ho Kim, Kyung-Sun Heo, Chang-Seon Myung
Atherothrombosis is one of the main underlying cause of cardiovascular diseases. In addition to treating atherothrombosis with antithrombotic agents, there is growing interest in the role of natural food products and biologically active ingredients for the prevention and treatment of cardiovascular diseases. This study aimed to investigate the effect of secolincomolide A (3) isolated from Lindera obtusiloba Blume on platelet activity and identify possible signaling pathways. In our study, the antiplatelet activities of 3 were measured by collagen-induced platelet aggregation and serotonin secretion in freshly isolated rabbit platelets...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28857681/expression-and-purification-of-the-extracellular-domains-of-human-glycoprotein-vi-gp-vi-and-the-receptor-for-advanced-glycation-end-products-rage-from-rattus-norvegicus-in-leishmania-tarentolae
#8
Thomas Langer, Carsten Corvey, Katja Kroll, Oliver Boscheinen, Thomas Wendrich, Werner Dittrich
Glycosylation is one of the most complex posttranslational modifications and may have significant influence on the proper function of the corresponding proteins. Bacteria and yeast are, because of easy handling and cost reasons, the most frequently used systems for recombinant protein expression. Bacteria generally do not glycosylate proteins and yeast might tend to hyperglycosylate. Insect cell and mammalian cell based expression system are able to produce complex N-glycosylation structures, but are more complex to handle and more expensive...
August 31, 2017: Preparative Biochemistry & Biotechnology
https://www.readbyqxmd.com/read/28855423/plant-based-food-cyanidin-3-glucoside-modulates-human-platelet-glycoprotein-vi-signaling-and-inhibits-platelet-activation-and-thrombus-formation
#9
Yanling Yao, Yanqiu Chen, Reheman Adili, Thomas McKeown, Pingguo Chen, Guangheng Zhu, Dan Li, Wenhua Ling, Heyu Ni, Yan Yang
Background: Platelets play an important role in hemostasis, thrombosis, and atherosclerosis. Glycoprotein VI (GPVI) is a major platelet receptor that interacts with exposed collagen on injured vessel walls. Our previous studies have shown that anthocyanins (a type of natural plant pigment) attenuate platelet function; however, whether anthocyanins affect collagen-induced GPVI signaling remains unknown.Objective: The objective of this study was to explore the effects of cyanidin-3-glucoside (Cy-3-g, one of the major bioactive compounds in anthocyanins) on platelet activation and thrombosis and the GPVI signaling pathway...
October 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28751543/adpase-cd39-fused-to-glycoprotein-vi-fc-boosts-local-antithrombotic-effects-at-vascular-lesions
#10
Heidrun Degen, Oliver Borst, Melanie Ziegler, Ann-Katrin Mojica Munoz, Janina Jamasbi, Britta Walker, Silvia Göbel, Julia Fassbender, Kristin Adler, Richard Brandl, Götz Münch, Reinhard Lorenz, Wolfgang Siess, Meinrad Gawaz, Martin Ungerer
BACKGROUND: GPVI (Glycoprotein VI) is the essential platelet collagen receptor in atherothrombosis. Dimeric GPVI-Fc (Revacept) binds to GPVI binding sites on plaque collagen. As expected, it did not increase bleeding in clinical studies. GPVI-Fc is a potent inhibitor of atherosclerotic plaque-induced platelet aggregation at high shear flow, but its inhibition at low shear flow is limited. We sought to increase the platelet inhibitory potential by fusing GPVI-Fc to the ectonucleotidase CD39 (fusion protein GPVI-CD39), which inhibits local ADP accumulation at vascular plaques, and thus to create a lesion-directed dual antiplatelet therapy that is expected to lack systemic bleeding risks...
July 27, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28742189/novel-endogenous-negative-modulators-of-platelet-function-as-potential-anti-thrombotic-targets
#11
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28727490/comparison-of-the-release-of-micrornas-and-extracellular-vesicles-from-platelets-in-response-to-different-agonists
#12
Ashley R Ambrose, Mohammed A Alsahli, Sameer A Kurmani, Alison H Goodall
On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP...
July 20, 2017: Platelets
https://www.readbyqxmd.com/read/28598382/syk-activity-is-dispensable-for-platelet-gp1b-ix-v-signaling
#13
Rachit Badolia, John C Kostyak, Carol Dangelmaier, Satya P Kunapuli
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation...
June 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28598281/design-development-and-characterization-of-act017-a-humanized-fab-that-blocks-platelet-s-glycoprotein-vi-function-without-causing-bleeding-risks
#14
Kristell Lebozec, Martine Jandrot-Perrus, Gilles Avenard, Olivier Favre-Bulle, Philippe Billiald
Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties...
August 2017: MAbs
https://www.readbyqxmd.com/read/28597906/platelet-receptors-as-therapeutic-targets-past-present-and-future
#15
Janina Jamasbi, Keng Ayabe, Shinya Goto, Bernhard Nieswandt, Karlheinz Peter, Wolfgang Siess
Anti-platelet drugs reduce arterial thrombosis after plaque rupture and erosion, prevent stent thrombosis and are used to prevent and treat myocardial infarction and ischaemic stroke. Some of them may also be helpful in treating less frequent diseases such as thrombotic thrombocytopenic purpura. The present concise review aims to cover current and future developments of anti-platelet drugs interfering with the interaction of von Willebrand factor (VWF) with glycoprotein (GP) Ibα, and directed against GPVI, GPIIb/IIIa (integrin αIIbβ3), the thrombin receptor PAR-1, and the ADP receptor P2Y12...
June 28, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28596377/trowaglerix-venom-polypeptides-as-a-novel-antithrombotic-agent-by-targeting-immunoglobulin-like-domains-of-glycoprotein-vi-in-platelet
#16
Chien-Hsin Chang, Ching-Hu Chung, Yi-Shu Tu, Cheng-Chieh Tsai, Chun-Chieh Hsu, Hui-Chin Peng, Yufeng J Tseng, Tur-Fu Huang
OBJECTIVE: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic. APPROACH AND RESULTS: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix α subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein)...
July 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28569920/recombinant-gpvi-fc-added-to-single-or-dual-antiplatelet-therapy-in-vitro-prevents-plaque-induced-platelet-thrombus-formation
#17
Ann-Katrin Mojica Muñoz, Janina Jamasbi, Kerstin Uhland, Heidrun Degen, Götz Münch, Martin Ungerer, Richard Brandl, Remco Megens, Christian Weber, Reinhard Lorenz, Wolfgang Siess
The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y12 antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque...
August 1, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28536721/differential-integrin-activity-mediated-by-platelet-collagen-receptor-engagement-under-flow-conditions
#18
Nicholas Pugh, Ben D Maddox, Dominique Bihan, Kirk A Taylor, Martyn P Mahaut-Smith, Richard W Farndale
The platelet receptors glycoprotein (Gp)VI, integrin α2β1 and GpIb/V/IX mediate platelet adhesion and activation during thrombogenesis. Increases of intracellular Ca(2+) ([Ca(2+)]i) are key signals during platelet activation; however, their relative importance in coupling different collagen receptors to functional responses under shear conditions remains unclear. To study shear-dependent, receptor-specific platelet responses, we used collagen or combinations of receptor-specific collagen-mimetic peptides as substrates for platelet adhesion and activation in whole human blood under arterial flow conditions and compared real-time and endpoint parameters of thrombus formation alongside [Ca(2+)]i measurements using confocal imaging...
July 26, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28523478/anti-gpvi-fab-sar264565-effectively-blocks-gpvi-function-in-ex-vivo-human-platelets-under-arterial-shear-in-a-perfusion-chamber
#19
Peter Florian, Peter Wonerow, Sebastian Harder, Karina Kuczka, Michel Dubar, Jochen Graff
INTRODUCTION: Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. METHODS: The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow...
August 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28441661/defective-platelet-activation-and-bleeding-complications-upon-cholestasis-in-mice
#20
Nina Sarah Gowert, Meike Klier, Maria Reich, Friedrich Reusswig, Lili Donner, Verena Keitel, Dieter Häussinger, Margitta Elvers
BACKGROUND/AIMS: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. METHODS: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice...
2017: Cellular Physiology and Biochemistry
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