Von Willebrand Factor Mutation Promotes Thrombocytopathy by Inhibiting Integrin Αiibβ3
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Distinct but Critical Roles for Integrin Aiibb3 in Platelet Lamellipodia Formation on Fibrinogen, Collagen-Related Peptide and T
Distinct but critical roles for integrin aIIbb3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin Kelly Thornber1, Owen J. T. McCarty2,3, Steve P. Watson2 and Catherine J. Pears1 1 Department of Biochemistry, University of Oxford, UK 2 Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, UK 3 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA Keywords Integrins are the major receptor type known to facilitate cell adhesion and aIIbb3; adhesion; integrins; lamellipodia; lamellipodia formation on extracellular matrix proteins. However, collagen- platelets related peptide and thrombin have recently been shown to mediate platelet lamellipodia formation when presented as immobilized surfaces. The aims Correspondence C. Pears, Department of Biochemistry, of this study were to establish if there exists a role for the platelet integrin South Parks Road, University of Oxford, aIIbb3 in this response; and if so, whether signalling from the integrin is Oxford, OX1 3QU, UK required for lamellipodia formation on these surfaces. Real-time analysis Fax: +44 1865 275259 was used to compare platelet morphological changes on surfaces of fibrino- Tel: +44 1865 275737 gen, collagen-related peptide or thrombin in the presence of various E-mail: [email protected] pharmacological inhibitors and platelets from ‘knockout’ mice. We demon- Website: http://www.bioch.ox.ac.uk strate that collagen-related peptide and thrombin stimulate distinct patterns 2+ (Received 11 July 2006, revised 22 August of platelet lamellipodia formation and elevation of intracellular Ca to 2006, accepted 12 September 2006) that induced by the integrin aIIbb3 ligand, fibrinogen. -
Urokinase, a Promising Candidate for Fibrinolytic Therapy for Intracerebral Hemorrhage
LABORATORY INVESTIGATION J Neurosurg 126:548–557, 2017 Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage *Qiang Tan, MD,1 Qianwei Chen, MD1 Yin Niu, MD,1 Zhou Feng, MD,1 Lin Li, MD,1 Yihao Tao, MD,1 Jun Tang, MD,1 Liming Yang, MD,1 Jing Guo, MD,2 Hua Feng, MD, PhD,1 Gang Zhu, MD, PhD,1 and Zhi Chen, MD, PhD1 1Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing; and 2Department of Neurosurgery, 211st Hospital of PLA, Harbin, People’s Republic of China OBJECTIVE Intracerebral hemorrhage (ICH) is associated with a high rate of mortality and severe disability, while fi- brinolysis for ICH evacuation is a possible treatment. However, reported adverse effects can counteract the benefits of fibrinolysis and limit the use of tissue-type plasminogen activator (tPA). Identifying appropriate fibrinolytics is still needed. Therefore, the authors here compared the use of urokinase-type plasminogen activator (uPA), an alternate thrombolytic, with that of tPA in a preclinical study. METHODS Intracerebral hemorrhage was induced in adult male Sprague-Dawley rats by injecting autologous blood into the caudate, followed by intraclot fibrinolysis without drainage. Rats were randomized to receive uPA, tPA, or saline within the clot. Hematoma and perihematomal edema, brain water content, Evans blue fluorescence and neurological scores, matrix metalloproteinases (MMPs), MMP mRNA, blood-brain barrier (BBB) tight junction proteins, and nuclear factor–κB (NF-κB) activation were measured to evaluate the effects of these 2 drugs in ICH. RESULTS In comparison with tPA, uPA better ameliorated brain edema and promoted an improved outcome after ICH. -
Hemoglobin Interaction with Gp1ba Induces Platelet Activation And
ARTICLE Platelet Biology & its Disorders Hemoglobin interaction with GP1bα induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis Rashi Singhal,1,2,* Gowtham K. Annarapu,1,2,* Ankita Pandey,1 Sheetal Chawla,1 Amrita Ojha,1 Avinash Gupta,1 Miguel A. Cruz,3 Tulika Seth4 and Prasenjit Guchhait1 1Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India; 2Biotechnology Department, Manipal University, Manipal, Karnataka, India; 3Thrombosis Research Division, Baylor College of Medicine, Houston, TX, USA, and 4Hematology, All India Institute of Medical Sciences, New Delhi, India *RS and GKA contributed equally to this work. ABSTRACT Intravascular hemolysis increases the risk of hypercoagulation and thrombosis in hemolytic disorders. Our study shows a novel mechanism by which extracellular hemoglobin directly affects platelet activation. The binding of Hb to glycoprotein1bα activates platelets. Lower concentrations of Hb (0.37-3 mM) significantly increase the phos- phorylation of signaling adapter proteins, such as Lyn, PI3K, AKT, and ERK, and promote platelet aggregation in vitro. Higher concentrations of Hb (3-6 mM) activate the pro-apoptotic proteins Bak, Bax, cytochrome c, caspase-9 and caspase-3, and increase platelet clot formation. Increased plasma Hb activates platelets and promotes their apoptosis, and plays a crucial role in the pathogenesis of aggregation and development of the procoagulant state in hemolytic disorders. Furthermore, we show that in patients with paroxysmal nocturnal hemoglobinuria, a chronic hemolytic disease characterized by recurrent events of intravascular thrombosis and thromboembolism, it is the elevated plasma Hb or platelet surface bound Hb that positively correlates with platelet activation. -
Cpla2pathway in the Regulation of Platelet Apoptosis Induced by ABT
Citation: Cell Death and Disease (2013) 4, e931; doi:10.1038/cddis.2013.459 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Dual role of the p38 MAPK/cPLA2 pathway in the regulation of platelet apoptosis induced by ABT-737 and strong platelet agonists N Rukoyatkina1,2, I Mindukshev2, U Walter3 and S Gambaryan*,1,2 p38 Mitogen-activated protein (MAP) kinase is involved in the apoptosis of nucleated cells. Although platelets are anucleated cells, apoptotic proteins have been shown to regulate platelet lifespan. However, the involvement of p38 MAP kinase in platelet apoptosis is not yet clearly defined. Therefore, we investigated the role of p38 MAP kinase in apoptosis induced by a mimetic of BH3-only proteins, ABT-737, and in apoptosis-like events induced by such strong platelet agonists as thrombin in combination with convulxin (Thr/Cvx), both of which result in p38 MAP kinase phosphorylation and activation. A p38 inhibitor (SB202190) inhibited the apoptotic events induced by ABT-737 but did not influence those induced by Thr/Cvx. The inhibitor also reduced the phosphorylation of cytosolic phospholipase A2 (cPLA2), an established p38 substrate, induced by ABT-737 or Thr/Cvx. ABT-737, but not Thr/Cvx, induced the caspase 3-dependent cleavage and inactivation of cPLA2. Thus, p38 MAPK promotes ABT-737- induced apoptosis by inhibiting the cPLA2/arachidonate pathway. We also show that arachidonic acid (AA) itself and in combination with Thr/Cvx or ABT-737 at low concentrations prevented apoptotic events, whereas at high concentrations it enhanced such events. -
Molecular Priming of Lyn by GPVI Enables an Immune Receptor to Adopt a Hemostatic Role
Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role Alec A. Schmaiera,b, Zhiying Zoua,b, Arunas Kazlauskasc, Lori Emert-Sedlakd, Karen P. Fonga,e, Keith B. Neevesf, Sean F. Maloneyg,h, Scott L. Diamondg,h, Satya P. Kunapulii, Jerry Warej, Lawrence F. Brassa,e, Thomas E. Smithgalld, Kalle Sakselac, and Mark L. Kahna,b,1 aDepartment of Medicine, bDivision of Cardiology, eDivision of Hematology, gDepartment of Chemical and Biomolecular Engineering, hInstitute for Medicine and Engineering, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; cDepartment of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Finland; dMicrobiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; iThe Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140; jDepartment of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and fDepartment of Chemical Engineering, Colorado School of Mines, Golden, CO 80401 Edited by Shaun R. Coughlin, University of California, San Francisco, CA, and approved October 12, 2009 (received for review June 10, 2009) The immune receptor signaling pathway is used by nonimmune cells, (5, 6). This pathway, like the established G protein-coupled signaling but the molecular adaptations that underlie its functional diversifi- pathways that mediate platelet activation by thrombin and ADP, results cation are not known. Circulating platelets use the immune receptor in the elevation of intracellular calcium levels and platelet activation homologue glycoprotein VI (GPVI) to respond to collagen exposed at responses, including granule release and integrin conformational sites of vessel injury. -
Single Platelet Variability Governs Population Sensitivity and Initiates
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.22.915512; this version posted January 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Single platelet variability governs population sensitivity and 2 initiates intrinsic heterotypic behaviours 3 Maaike S. A. Jongen1, Ben D. MacArthur1,2,3, Nicola A. Englyst1,3 and Jonathan West1,3,* 4 1. Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK 5 2. Mathematical Sciences, University of Southampton, Southampton SO17 1BJ, UK 6 3. Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK 7 *Correspondence to: [email protected] 8 9 Abstract 10 Droplet microfluidics combined with flow cytometry was used for high throughput single platelet function 11 analysis. A large-scale sensitivity continuum was shown to be a general feature of human platelets from 12 individual donors, with hypersensitive platelets coordinating significant sensitivity gains in bulk platelet 13 populations and shown to direct aggregation in droplet-confined minimal platelet systems. Sensitivity gains 14 scaled with agonist potency (convulxin>TRAP-14>ADP) and reduced the collagen and thrombin activation 15 threshold required for platelet population polarization into pro-aggregatory and pro-coagulant states. The 16 heterotypic platelet response results from an intrinsic behavioural program. The method and findings invite 17 future discoveries into the nature of hypersensitive platelets and how community effects produce population 18 level behaviours in health and disease. -
A Microfluidic Approach for Evaluating Novel Antithrombotic Targets
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 A Microfluidic Approach For Evaluating Novel Antithrombotic Targets Shu Zhu University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Chemical Engineering Commons Recommended Citation Zhu, Shu, "A Microfluidic Approach For Evaluating Novel Antithrombotic Targets" (2017). Publicly Accessible Penn Dissertations. 2670. https://repository.upenn.edu/edissertations/2670 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2670 For more information, please contact [email protected]. A Microfluidic Approach For Evaluating Novel Antithrombotic Targets Abstract Microfluidic systems allow precise control of the anticoagulation/pharmacology protocols, defined reactive surfaces, hemodynamic flow and optical imaging outines,r and thus are ideal for studies of platelet function and coagulation response. This thesis describes the use of a microfluidic approach to investigate the role of the contact pathway factors XII and XI, platelet-derived polyphosphate, and thiol isomerases in thrombus growth and to evaluate their potential as safer antithrombotic drug targets. The use of low level of corn trypsin inhibitor allowed the study of the contact pathway on collagen/kaolin surfaces with minimally disturbed whole blood sample and we demonstrated the sensitivity of this assay to antithrombotic drugs. On collagen/tissue factor surfaces, we found -
A Guide for People Living with Von Willebrand Disorder CONTENTS
A guide for people living with von Willebrand disorder CONTENTS What is von Willebrand disorder (VWD)?................................... 3 Symptoms............................................................................................... 5 Types of VWD...................................................................................... 6 How do you get VWD?...................................................................... 7 VWD and blood clotting.................................................................... 11 Diagnosis................................................................................................. 13 Treatment............................................................................................... 15 Taking care of yourself or your child.............................................. 19 (Education, information, first aid/medical emergencies, medication to avoid) Living well with VWD......................................................................... 26 (Sport, travel, school, telling others, work) Special issues for women and girls.................................................. 33 Connecting with others..................................................................... 36 Can I live a normal life with von Willebrand disorder?............. 37 More information................................................................................. 38 2 WHAT IS VON WILLEBRAND DISORDER (VWD)? Von Willebrand disorder (VWD) is an inherited bleeding disorder. People with VWD have a problem with a protein -
Fibrin Induces Release of Von Willebrand Factor from Endothelial Cells
Fibrin induces release of von Willebrand factor from endothelial cells. J A Ribes, … , C W Francis, D D Wagner J Clin Invest. 1987;79(1):117-123. https://doi.org/10.1172/JCI112771. Research Article Addition of fibrinogen to human umbilical vein endothelial cells in culture resulted in release of von Willebrand factor (vWf) from Weibel-Palade bodies that was temporally related to formation of fibrin in the medium. Whereas no release occurred before gelation, the formation of fibrin was associated with disappearance of Weibel-Palade bodies and development of extracellular patches of immunofluorescence typical of vWf release. Release also occurred within 10 min of exposure to preformed fibrin but did not occur after exposure to washed red cells, clot liquor, or structurally different fibrin prepared with reptilase. Metabolically labeled vWf was immunopurified from the medium after release by fibrin and shown to consist of highly processed protein lacking pro-vWf subunits. The contribution of residual thrombin to release stimulated by fibrin was minimized by preparing fibrin clots with nonstimulatory concentrations of thrombin and by inhibiting residual thrombin with hirudin or heating. We conclude that fibrin formed at sites of vessel injury may function as a physiologic secretagogue for endothelial cells causing rapid release of stored vWf. Find the latest version: https://jci.me/112771/pdf Fibrin Induces Release of von Willebrand Factor from Endothelial Cells Julie A. Ribes, Charles W. Francis, and Denisa D. Wagner Hematology Unit, Department ofMedicine, University ofRochester School ofMedicine and Dentistry, Rochester, New York 14642 Abstract erogeneous and can be separated by sodium dodecyl sulfate (SDS) electrophoresis into a series of disulfide-bonded multimers Addition of fibrinogen to human umbilical vein endothelial cells with molecular masses from 500,000 to as high as 20,000,000 in culture resulted in release of von Willebrand factor (vWf) D (8). -
Urokinase Plasminogen Activator: a Potential Thrombolytic Agent for Ischaemic Stroke
Urokinase Plasminogen Activator: A Potential Thrombolytic Agent for Ischaemic Stroke Rais Reskiawan A. Kadir1, Ulvi Bayraktutan1 1Stroke, Division of Clinical Neuroscience, School of Medicine, The University of Nottingham Address for correspondence: Dr. Ulvi Bayraktutan Associate Professor Stroke, Division of Clinical Neuroscience, School of Medicine, The University of Nottingham, Clinical Sciences Building, Hucknall Road, Nottingham NG5 1PB, United Kingdom (UK) Tel: +44-(115) 8231764 Fax: +44-(115) 8231767 E-mail: [email protected] 1 Abstract Stroke continues to be one of the leading causes of mortality and morbidity worldwide. Restoration of cerebral blood flow by recombinant plasminogen activator (rtPA) with or without mechanical thrombectomy is considered the most effective therapy for rescuing brain tissue from ischaemic damage, but this requires advanced facilities and highly skilled professionals, entailing high costs, thus in resource-limited contexts urokinase plasminogen activator (uPA) is commonly used as an alternative. This literature review summarises the existing studies relating to the potential clinical application of uPA in ischaemic stroke patients. In translational studies of ischaemic stroke, uPA has been shown to promote nerve regeneration and reduce infarct volume and neurological deficits. Clinical trials employing uPA as a thrombolytic agent have replicated these favourable outcomes and reported consistent increases in recanalisation, functional improvement, and cerebral haemorrhage rates, similar to those observed with rtPA. Single-chain zymogen pro-urokinase (pro-uPA) and rtPA appear to be complementary and synergistic in their action, suggesting that their co-administration may improve the efficacy of thrombolysis without affecting the overall risk of haemorrhage. Large clinical trials examining the efficacy of uPA or the combination of pro-uPA and rtPA are desperately required to unravel whether either therapeutic approach may be a safe first-line treatment option for patients with ischaemic stroke. -
Recommended Abbreviations for Von Willebrand Factor and Its Activities
RECOMMENDED ABBREVIATIONS FOR VON WILLEBRAND FACTOR AND ITS ACTIVITIES On behalf of the von Willebrand Factor Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Claudine Mazurier and Francesco Rodeghiero Previous official recommendations concerning the abbreviations for von Willebrand Factor (and factor VIII) are 15 years old and were limited to "vWf" for the protein and "vWf:Ag" for the antigen (1). Nowadays, the various properties of von Willebrand Factor (ristocetin cofactor activity and capacity to bind to either collagen or factor VIII) are better defined and may warrant specific abbreviations. Furthermore, the protein synthesized by the von Willebrand factor gene is now abbreviated as pre-pro-VWF (2). Accordingly, the subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the ISTH has recommended new abbreviations for von Willebrand Factor antigen and its various activities, currently measured by immunologic or functional assays (Table I). It is hoped that a uniform application of the abbreviations recommended here will improve communication among scientists and clinicians, especially for those who are less familiar with the field. Table 1: Recommended abbreviations for von Willebrand Factor and its activities Attribute Recommended abbreviations Mature protein VWF Antigen VWF:Ag Ristocetin cofactor activity VWF:RCo Collagen binding capacity VWF:CB Factor VIII binding capacity VWF:FVIIIB REFERENCES: 1 – Marder VJ, Mannucci PM, Firkin BG, Hoyer LW and Meyer D. Standard nomenclature for factor VIII and von Willebrand factor: a recommendation by the International Committee on Thrombosis and Haemostasis. Thromb. Haemost. 1985, 54, 871-2. 2 – Goodeve AC, Eikenboom JCJ, Ginsburg D, Hilbert L, Mazurier C, Peake IR, Sadler JE, Rodeghiero F on behalf of the ISTH SSC subcommittee on von Willebrand Factor. -
Biomechanical Thrombosis: the Dark Side of Force and Dawn of Mechano- Medicine
Open access Review Stroke Vasc Neurol: first published as 10.1136/svn-2019-000302 on 15 December 2019. Downloaded from Biomechanical thrombosis: the dark side of force and dawn of mechano- medicine Yunfeng Chen ,1 Lining Arnold Ju 2 To cite: Chen Y, Ju LA. ABSTRACT P2Y12 receptor antagonists (clopidogrel, pras- Biomechanical thrombosis: the Arterial thrombosis is in part contributed by excessive ugrel, ticagrelor), inhibitors of thromboxane dark side of force and dawn platelet aggregation, which can lead to blood clotting and A2 (TxA2) generation (aspirin, triflusal) or of mechano- medicine. Stroke subsequent heart attack and stroke. Platelets are sensitive & Vascular Neurology 2019;0. protease- activated receptor 1 (PAR1) antag- to the haemodynamic environment. Rapid haemodynamcis 1 doi:10.1136/svn-2019-000302 onists (vorapaxar). Increasing the dose of and disturbed blood flow, which occur in vessels with these agents, especially aspirin and clopi- growing thrombi and atherosclerotic plaques or is caused YC and LAJ contributed equally. dogrel, has been employed to dampen the by medical device implantation and intervention, promotes Received 12 November 2019 platelet thrombotic functions. However, this platelet aggregation and thrombus formation. In such 4 Accepted 14 November 2019 situations, conventional antiplatelet drugs often have also increases the risk of excessive bleeding. suboptimal efficacy and a serious side effect of excessive It has long been recognized that arterial bleeding. Investigating the mechanisms of platelet thrombosis