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Platelet integrin

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https://www.readbyqxmd.com/read/29446689/platelets-and-vascular-integrity
#1
Carsten Deppermann
Platelets patrol the vasculature and adhere at sites of vascular damage after trauma to limit blood loss. In recent years, however, it has become clear that platelets also contribute to pathophysiologic processes such as thrombosis, atherosclerosis, stroke, sepsis and many more. An exciting new role for them is in non-classical hemostasis to prevent bleeding in the inflamed vasculature. Recent studies suggest that GPVI, CLEC-2, integrin αIIbβ3 (GPIIb/IIIa), and the content of platelet α- and dense granules are important players in this process...
February 15, 2018: Platelets
https://www.readbyqxmd.com/read/29419425/safety-and-efficacy-of-plerixafor-dose-escalation-for-the-mobilization-of-cd34-hematopoietic-progenitor-cells-in-patients-with-sickle-cell-disease-interim-results
#2
Farid Boulad, Tsiporah Shore, Koen van Besien, Caterina Minniti, Mihaela Barbu-Stevanovic, Sylvie Wiener Fedus, Fabiana Perna, June Greenberg, Danielle Guarneri, Vijay Nandi, Audrey Mauguen, Karina Yazdanbakhsh, Michel Sadelain, Patricia A Shi
Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cell harvest for transduction or gene editing. We therefore performed a Phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and 10 were on hydroxyurea. Of 8 patients achieving a CD34+ cell concentration >30 cells/μl, 6 were on hydroxyurea...
February 1, 2018: Haematologica
https://www.readbyqxmd.com/read/29385657/in-silico-analysis-of-structural-modifications-in-and-around-the-integrin-%C3%AE-iib-genu-caused-by-itga2b-variants-in-human-platelets-with-emphasis-on-glanzmann-thrombasthenia
#3
Xavier Pillois, Pierre Peters, Karin Segers, Alan T Nurden
BACKGROUND: Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the αIIbβ3 integrin in platelet aggregation. Stable bent αIIbβ3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The αIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the αIIb genu define GT phenotype. METHODS: Sanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT-causing missense mutations extending from the lower part of the β-propeller, and through the thigh and upper calf-1 domains...
January 31, 2018: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29381707/rasa3-controls-turnover-of-endothelial-cell-adhesion-and-vascular-lumen-integrity-by-a-rap1-dependent-mechanism
#4
Patricia Molina-Ortiz, Tanguy Orban, Maud Martin, Audrey Habets, Franck Dequiedt, Stéphane Schurmans
Rasa3 is a GTPase activating protein of the GAP1 family which targets R-Ras and Rap1. Although catalytic inactivation or deletion of Rasa3 in mice leads to severe hemorrhages and embryonic lethality, the biological function and cellular location of Rasa3 underlying these defects remains unknown. Here, using a combination of loss of function studies in mouse and zebrafish as well as in vitro cell biology approaches, we identify a key role for Rasa3 in endothelial cells and vascular lumen integrity. Specific ablation of Rasa3 in the mouse endothelium, but not in megakaryocytes and platelets, lead to embryonic bleeding and death at mid-gestation, recapitulating the phenotype observed in full Rasa3 knock-out mice...
January 30, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29380037/a-novel-heterozygous-itgb3-p-t720del-inducing-spontaneous-activation-of-integrin-%C3%AE-iib%C3%AE-3-in-autosomal-dominant-macrothrombocytopenia-with-aggregation-dysfunction
#5
Naohiro Miyashita, Masahiro Onozawa, Koji Hayasaka, Takahiro Yamada, Ohsuke Migita, Kenichiro Hata, Kohei Okada, Hideki Goto, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Shinji Kunishima, Takanori Teshima
We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin αIIbβ3 was partially activated in a resting status, but platelet expression of αIIbβ3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/β3 (p.T720del)-transfected 293T cells in suspension conditions...
January 29, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29369482/norcantharidin-a-clinical-used-chemotherapeutic-agent-acts-as-a-powerful-inhibitor-by-interfering-with-fibrinogen-integrin-%C3%AE-iib-%C3%AE-3-binding-in-human-platelets
#6
Chih-Hsuan Hsia, Wan-Jung Lu, Kuan-Hung Lin, Duen-Suey Chou, Pitchairaj Geraldine, Thanasekaran Jayakuma, Nen-Chung Chang, Joen-Rong Sheu
During platelet activation, fibrinogen binds to its specific platelet receptor, integrin αIIb β3 , thus completing the final common pathway for platelet aggregation. Norcantharidin (NCTD) is a promising anticancer agent in China from medicinal insect blister beetle. In this study, we provided the evidence to demonstrate NCTD (0.1-1.0 μM) possesses very powerful antiplatelet activity in human platelets; nevertheless, it had no effects on surface P-selectin expression and only slight inhibition on ATP-release reaction in activated platelets...
January 25, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29350833/platelets-kill-bacteria-by-bridging-innate-and-adaptive-immunity-via-pf4-and-fc%C3%AE-riia
#7
R Palankar, T P Kohler, K Krauel, J Wesche, S Hammerschmidt, A Greinacher
BACKGROUND: Activated platelets release the chemokine platelet factor 4 (PF4) stored in their granules. PF4 binds to polyanions (P) on bacteria, undergoes a conformational change and exposes neoepitopes. These neoepitopes induce production of anti-PF4/P antibodies. As PF4 binds to a variety of bacteria, anti-PF4/P IgG can bind and opsonize several bacterial species. OBJECTIVE: Here we investigated whether platelets are able to kill bacteria directly after recognizing anti-PF4/P IgG opsonized bacteria in the presence of PF4 via their FcγRIIA...
January 19, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29344719/phosphorylation-of-vasodilator-stimulated-phosphoprotein-contributes-to-myocardial-ischemic-preconditioning
#8
David Köhler, Sofia-Iris Bibli, Lothar P Klammer, Judith M Roth, Rainer Lehmann, Ingrid Fleming, Tiago F Granja, Andreas Straub, Peter M Benz, Peter Rosenberger
Ischemic preconditioning (IP) is a well-known strategy to protect organs against cell death following ischemia. The previous work has shown that vasodilator-stimulated phosphoprotein (VASP) is involved in cytoskeletal reorganization and that it holds significant importance for the extent of myocardial ischemia reperfusion injury. Yet, the role of VASP during myocardial IP is, to date, not known. We report here that VASP phosphorylation at serine157 and serine239 is induced during hypoxia in vitro and during IP in vivo...
January 17, 2018: Basic Research in Cardiology
https://www.readbyqxmd.com/read/29314633/leucocyte-and-platelet-rich-fibrin-a-carrier-of-autologous-multipotent-cells-for-regenerative-medicine
#9
Rosa Di Liddo, Thomas Bertalot, Alessio Borean, Ivan Pirola, Alberto Argentoni, Sandra Schrenk, Carola Cenzi, Stefano Capelli, Maria Teresa Conconi, Pier Paolo Parnigotto
The wound healing is a complex process wherein inflammation, proliferation and regeneration evolve according to a spatio-temporal pattern from the activation of coagulation cascade to the formation of a plug clot including fibrin matrix, blood-borne cells and cytokines/growth factors. Creating environments conducive to tissue repair, the haemoderivatives are commonly proposed for the treatment of hard-to-heal wounds. Here, we explored in vitro the intrinsic regenerative potentialities of a leucocyte- and platelet-rich fibrin product, known as CPL-MB, defining the stemness grade of cells sprouting from the haemoderivative...
January 5, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29297721/mucor-circinelloides-induces-platelet-aggregation-through-integrin-%C3%AE-iib%C3%AE-3-and-fc%C3%AE-riia
#10
Harlene Ghuman, Alicia Shepherd-Roberts, Stephanie Watson, Malou Zuidscherwoude, Steve P Watson, Kerstin Voelz
Thrombosis is a hallmark of the fatal fungal infection mucormycosis. Yet, the platelet activation pathway in response to mucormycetes is unknown. In this study we determined the platelet aggregation potential of Mucor circinelloides (M. circinelloides) NRRL3631, characterized the signaling pathway facilitating aggregation in response to fungal spores, and identified the influence of the spore developmental stage upon platelet aggregation potential. Using impedance and light-transmission aggregometry, we showed that M...
January 3, 2018: Platelets
https://www.readbyqxmd.com/read/29296957/%C3%AE-iib%C3%AE-3-binding-to-a-fibrinogen-fragment-lacking-the-%C3%AE-chain-dodecapeptide-is-activation-dependent-and-edta-inducible
#11
Hina Zafar, Yi Shang, Jihong Li, George A David, Joseph P Fernandez, Henrik Molina, Marta Filizola, Barry S Coller
Platelet integrin receptor αIIbβ3 supports platelet aggregation by binding fibrinogen. The interaction between the fibrinogen C-terminal γ-chain peptide composed of residues γ-404-411 (GAKQAGDV) and the Arg-Gly-Asp (RGD) binding pocket on αIIbβ3 is required for fibrinogen-mediated platelet aggregation, but data suggest that other ancillary binding sites on both fibrinogen and αIIbβ3 may lead to higher-affinity fibrinogen binding and clot retraction. To identify additional sites, we analyzed the ability of platelets and cells expressing normal and mutant αIIbβ3 to adhere to an immobilized fibrinogen plasmin fragment that lacks intact γ-404-411 ('D98')...
February 28, 2017: Blood Advances
https://www.readbyqxmd.com/read/29289806/protease-activated-receptor-4-par4-variant-influences-on-platelet-reactivity-induced-by-par4-activating-peptide-through-altered-ca2-mobilization-and-erk-phosphorylation-in-healthy-japanese-subjects
#12
Yoichiro Morikawa, Hisashi Kato, Hirokazu Kashiwagi, Nobuko Nishiura, Keigo Akuta, Shigenori Honda, Yuzuru Kanakura, Yoshiaki Tomiyama
BACKGROUND: Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear. OBJECTIVES: We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant...
December 24, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/29274201/itraq-based-proteomic-analysis-reveals-protein-profile-in-plasma-from-children-with-autism
#13
Liming Shen, Kaoyuan Zhang, Chengyun Feng, Youjiao Chen, Shuiming Li, Javed Iqbal, Liping Liao, Yuxi Zhao, Jian Zhai
PURPOSE: Autism is a childhood neurological disorder with poorly understood etiology and pathology. This study is designed to identify differentially expressed proteins which might serve as potential biomarkers for autism. EXPERIMENTAL DESIGN: We performed iTRAQ (isobaric tags for relative and absolute quantitation) analysis for normal and autistic children's plasma of the same age group. RESULTS: The results showed that 24 differentially expressed proteins were identified between autistic subjects and controls...
December 23, 2017: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/29258493/antiplatelet-mechanism-of-an-herbal-mixture-prepared-from-the-extracts-of-phyllostachys-pubescens-leaves-and-prunus-mume-fruits
#14
Eunjung Son, Seung-Hyung Kim, Won-Kyung Yang, Dong-Seon Kim, Jimin Cha
BACKGROUND: Bamboo (Phyllostachys pubescens) leaves and Japanese apricot (Mume fructus) fruit are traditionally recognized to be safe herbs broadly used for food and medicinal purposes in Southeast Asia. Our group previously explored their antiplatelet effects. This study was designed to confirm inhibition effects of PM21 (a 2:1 mixture of bamboo leaf extract and Japanese apricot fruit extract) on platelet aggregation and evaluate its potency to use as an herbal remedy to prevent and/or treat the diseases caused by platelet aggregation and thrombus formation...
December 19, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/29247535/the-role-of-extracellular-matrix-stiffness-in-megakaryocyte-and-platelet-development-and-function
#15
REVIEW
Orly Leiva, Catherine Leon, Seng Kah Ng, Pierre Mangin, Christian Gachet, Katya Ravid
The extracellular matrix (ECM) is a key acellular structure in constant remodeling to provide tissue cohesion and rigidity. Deregulation of the balance between matrix deposition, degradation, and crosslinking results in fibrosis. Bone marrow fibrosis (BMF) is associated with several malignant and nonmalignant pathologies severely affecting blood cell production. BMF results from abnormal deposition of collagen fibers and enhanced lysyl oxidase-mediated ECM crosslinking within the marrow, thereby increasing marrow stiffness...
December 16, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29242851/in-depth-ptdins-3-4-5-p3-signalosome-analysis-identifies-dapp1-as-a-negative-regulator-of-gpvi-driven-platelet-function
#16
Tom N Durrant, James L Hutchinson, Kate J Heesom, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Aaron J Marshall, Samantha F Moore, Ingeborg Hers
The class I phosphoinositide 3-kinase (PI3K) isoforms play important roles in platelet priming, activation, and stable thrombus formation. Class I PI3Ks predominantly regulate cell function through their catalytic product, the signaling phospholipid phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], which coordinates the localization and/or activity of a diverse range of binding proteins. Notably, the complete repertoire of these class I PI3K effectors in platelets remains unknown, limiting mechanistic understanding of class I PI3K-mediated control of platelet function...
June 13, 2017: Blood Advances
https://www.readbyqxmd.com/read/29242293/variable-impairment-of-platelet-functions-in-patients-with-severe-genetically-linked-immune-deficiencies
#17
Magdolna Nagy, Tom G Mastenbroek, Nadine J A Mattheij, Susanne de Witt, Kenneth J Clemetson, Janbernd Kirschner, Ansgar S Schulz, Thomas Vraetz, Carsten Speckmann, Attila Braun, Judith M E M Cosemans, Barbara Zieger, Johan W M Heemskerk
In patients with dysfunctions of the Ca2+ channel ORAI1, stromal interaction molecule 1 (STIM1) or integrin-regulating kindlin-3 (FERMT3), severe immunodeficiency is frequently linked to abnormal platelet activity. In this paper, we studied in nine rare patients, including relatives, with confirmed genetic mutations of ORAI1, STIM1 or FERMT3, platelet responsiveness by multi-parameter assessment of whole blood thrombus formation under high-shear flow conditions. In platelets isolated from 5 out of 6 patients with ORAI1 or STIM1 mutations, store-operated Ca2+ entry (SOCE) was (in)completely defective compared to control platelets...
December 14, 2017: Haematologica
https://www.readbyqxmd.com/read/29240434/fibrinogen-motif-discriminates-platelet-and-cell-capture-at-peptide-modified-gold-micropore-arrays
#18
Kellie Adamson, Elaine Spain, Una Prendergast, Niamh Moran, Robert J Forster, Tia E Keyes
Human blood platelets and SK-N-AS neuroblastoma cancer cell capture at spontaneously adsorbed monolayers of fibrinogen binding motifs GRGDS (generic integrin adhesion), HHLGGAKQAGDV (exclusive to platelet integrin αIIbβ3) or octanethiol (adhesion inhibitor) at planar gold and ordered 1.6 micron diameter spherical cap gold cavity arrays was compared. In all cases, RGD promoted capture while alkanethiol monolayers inhibited adhesion. Conversely only platelets adhered to AGD modified surfaces, indicating the AGD motif is recognized preferentially by the platelet specific integrin, αIIbβ3...
December 14, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
https://www.readbyqxmd.com/read/29230812/the-gut-microbiota-an-emerging-risk-factor-for-cardiovascular-and-cerebrovascular-disease
#19
REVIEW
Stefanie Ascher, Christoph Reinhardt
Commensal gut microbiota have recently been implicated in cardiovascular disease (CVD) and cerebrovascular disease. Atherosclerotic plaque formation depends on the colonization status of the host. In addition to host nutrition and the related microbiota-dependent metabolic changes, activation of innate immune pathways triggers the development of atherosclerosis and supports arterial thrombosis. Gnotobiotic mouse models have uncovered that activation of Toll-like receptor-2 by gut microbial ligands supports von Willebrand factor-integrin mediated platelet deposition to the site of vascular injury...
December 12, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29227167/diagnosis-of-platelet-function-disorders-a-standardized-rational-and-modular-flow-cytometric-approach
#20
Oliver Andres, Katja Henning, Gabriele Strauß, Annerose Pflug, Georgi Manukjan, Harald Schulze
A high proportion of patients with mucocutaneous bleeding diathesis and suspected inherited or acquired platelet disorder remain without diagnosis even after comprehensive laboratory testing. Since flow cytometry allows investigation of resting and activated platelets on the single cell level by requiring only minimal amounts of blood, this method has become an important assay within the diagnostic algorithm, especially in pediatrics. We therefore developed a standardized and modular flow cytometric approach that contributes to clarify impaired platelet function in a rational step-by-step manner...
December 11, 2017: Platelets
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