Relationship Between Circulating Tumor Cells and Tissue
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Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E. -
The Two Faces of Thrombosis: Coagulation Cascade and Platelet Aggregation. Are Platelets the Main Therapeutic Target
Thrombosis and Circulation Open Access Cimmino et al., J Thrombo Cir 2017, 3:1 Review Article Open Access The Two Faces of Thrombosis: Coagulation Cascade and Platelet Aggregation. Are Platelets the Main Therapeutic Target? Giovanni Cimmino*, Salvatore Fischetti and Paolo Golino Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy *Corresponding author: Giovanni Cimmino, MD, PhD, Department of Cardio-Thoracic and Respiratory Sciences, Section of Cardiology, University of Campania “Luigi Vanvitelli”, via Leonardo Bianchi, 180131 Naples, Italy. Tel: +39-081-7064175, Fax: +39-081-7064234; E-mail: [email protected] Received date: Dec 28, 2016, Accepted date: Jan 27, 2017, Published date: Jan 31, 2017 Copyright: © 2017 Giovanni C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Acute thrombus formation is the pathophysiological substrate underlying several clinical conditions, such as acute coronary syndrome (ACS) and stroke. Activation of coagulation cascade is a key step of the thrombotic process: vessel injury results in exposure of the glycoprotein tissue factor (TF) to the flowing blood. Once exposed, TF binds factor VII/VIIa (FVII/FVIIa) and in presence of calcium ions, it forms a tertiary complex able to activate FX to FXa, FIX to FIXa, and FVIIa itself. The final step is thrombin formation at the site of vessel injury with subsequent platelet activation, fibrinogen to fibrin conversion and ultimately thrombus formation. Platelets are the key cells in primary hemostasis. -
RIASTAP®, Fibrinogen Concentrate (Human) Lyophilized Powder for Solution for Intravenous Injection
HIGHLIGHTS OF PRESCRIBING INFORMATION -------------------------------------CONTRAINDICATIONS ------------------------------------ These highlights do not include all the information needed to use RIASTAP • Known anaphylactic or severe systemic reactions to human plasma-derived products (4). safely and effectively. See full prescribing information for RIASTAP. ---------------------------------WARNINGS AND PRECAUTIONS---------------------------- RIASTAP®, Fibrinogen Concentrate (Human) • Monitor patients for early signs of anaphylaxis or hypersensitivity reactions and if necessary, discontinue administration and institute appropriate treatment (5.1). Lyophilized Powder for Solution for Intravenous Injection • Thrombotic events have been reported in patients receiving RIASTAP. Weigh the benefits of administration versus the risks of thrombosis (5.2). Initial U.S. Approval: 2009 • Because RIASTAP is made from human blood, it may carry a risk of transmitting ------------------------------------RECENT MAJOR CHANGES--------------------------------- infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent Indications and Usage (1) 06/2021 and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.3). Dosage and Administration (2.2) 07/2020 -------------------------------------ADVERSE REACTIONS-------------------------------------- ----------------------------------INDICATIONS AND USAGE----------------------------------- • The most serious adverse reactions observed are thrombotic episodes (pulmonary RIASTAP, Fibrinogen -
Platelet Surface Glycoproteins. Studies on Resting and Activated Platelets and Platelet Membrane Microparticles in Normal Subjec
Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J N George, … , N Kieffer, P J Newman J Clin Invest. 1986;78(2):340-348. https://doi.org/10.1172/JCI112582. Research Article The accurate definition of surface glycoprotein abnormalities in circulating platelets may provide better understanding of bleeding and thrombotic disorders. Platelet surface glycoproteins were measured on intact platelets in whole blood and platelet membrane microparticles were assayed in cell-free plasma using 125I-monoclonal antibodies. The glycoproteins (GP) studied were: GP Ib and GP IIb-IIIa, two of the major intrinsic plasma membrane glycoproteins; GMP-140, an alpha- granule membrane glycoprotein that becomes exposed on the platelet surface following secretion; and thrombospondin (TSP), an alpha-granule secreted glycoprotein that rebinds to the platelet surface. Thrombin-induced secretion in normal platelets caused the appearance of GMP-140 and TSP on the platelet surface, increased exposure of GP IIb-IIIa, and decreased antibody binding to GP Ib. Patients with adult respiratory distress syndrome had an increased concentration of GMP-140 and TSP on the surface of their platelets, demonstrating in vivo platelet secretion, but had no increase of platelet microparticles in their plasma. In contrast, patients after cardiac surgery with cardiopulmonary bypass demonstrated changes consistent with membrane fragmentation without secretion: a decreased platelet surface concentration of GP Ib and GP IIb with no increase of GMP-140 and TSP, and an increased plasma concentration of platelet membrane microparticles. These methods will help to define acquired abnormalities of platelet surface glycoproteins. -
Factor V Leiden Thrombophilia
Factor V Leiden thrombophilia Description Factor V Leiden thrombophilia is an inherited disorder of blood clotting. Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels. People with factor V Leiden thrombophilia have a higher than average risk of developing a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the legs, although they can also occur in other parts of the body, including the brain, eyes, liver, and kidneys. Factor V Leiden thrombophilia also increases the risk that clots will break away from their original site and travel through the bloodstream. These clots can lodge in the lungs, where they are known as pulmonary emboli. Although factor V Leiden thrombophilia increases the risk of blood clots, only about 10 percent of individuals with the factor V Leiden mutation ever develop abnormal clots. The factor V Leiden mutation is associated with a slightly increased risk of pregnancy loss (miscarriage). Women with this mutation are two to three times more likely to have multiple (recurrent) miscarriages or a pregnancy loss during the second or third trimester. Some research suggests that the factor V Leiden mutation may also increase the risk of other complications during pregnancy, including pregnancy-induced high blood pressure (preeclampsia), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). However, the association between the factor V Leiden mutation and these complications has not been confirmed. Most women with factor V Leiden thrombophilia have normal pregnancies. -
Coagadex, Human Coagulation Factor X
26 July 2018 EMA/CHMP/455550/2018 Committee for Medicinal Products for Human Use (CHMP) CHMP extension of indication variation assessment report Coagadex International non-proprietary name: human coagulation factor X Procedure No. EMEA/H/C/003855/II/0007 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 5 1.1. Type II variation .................................................................................................. 5 1.2. Steps taken for the assessment of the product ......................................................... 6 2. Scientific discussion ................................................................................ 6 2.1. Introduction......................................................................................................... 6 2.2. Non-clinical aspects .............................................................................................. 7 2.3. Clinical aspects .................................................................................................... 7 2.3.1. Introduction ..................................................................................................... -
Factor V Leiden Thrombophilia Jody Lynn Kujovich, MD
GENETEST REVIEW Genetics in Medicine Factor V Leiden thrombophilia Jody Lynn Kujovich, MD TABLE OF CONTENTS Pathogenic mechanisms and molecular basis.................................................2 Obesity ...........................................................................................................8 Prevalence..............................................................................................................2 Surgery...........................................................................................................8 Diagnosis................................................................................................................2 Thrombosis not convincingly associated with Factor V Leiden....................8 Clinical diagnosis..............................................................................................2 Arterial thrombosis...........................................................................................8 Testing................................................................................................................2 Myocardial infarction.......................................................................................8 Indications for testing......................................................................................3 Stroke .................................................................................................................8 Natural history and clinical manifestations......................................................3 Genotype-phenotype -
Complement Activation in Factor D-Deficient Mice
Complement activation in factor D-deficient mice Yuanyuan Xu*†, Minghe Ma‡, Gregory C. Ippolito*, Harry W. Schroeder, Jr.*, Michael C. Carroll‡, and John E. Volanakis*§ *Department of Medicine, University of Alabama, Birmingham, AL 35294; ‡Department of Pathology, Harvard Medical School, Boston, MA 02138; and §Biomedical Sciences Research Center ‘‘A. Fleming,’’ Vari 166 72, Greece Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 18, 2001 (received for review August 15, 2001) To assess the contribution of the alternative pathway in comple- mice. The results indicate that factor D is indispensable for ment activation and host defense and its possible role in the complement activation through the AP and that it plays a regulation of systemic energy balance in vivo, factor D-deficient significant role in opsonization of bacteria by ‘‘natural’’ IgM mice were generated by gene targeting. The mutant mice have no antibody. It is also shown that factor D does not play a major role apparent abnormality in development and their body weights are in fat metabolism. Interestingly, the data revealed a unique mode similar to those of factor D-sufficient littermates. Complement of factor B activation, which provides valuable insights into the activation could not be initiated in the serum of deficient mice by mechanism of AP activation. the alternative pathway activators rabbit erythrocytes and zymo- san. Surprisingly, injection of cobra venom factor (CVF) caused a Materials and Methods profound and reproducible reduction in serum C3 levels, whereas, Generation of Factor D-Deficient Mice. A gene targeting vector, as expected, there was no C3 reduction in factor B-deficient mice Adn͞TK, was constructed (9) on the backbone of pBluescript treated similarly. -
PROTEIN C DEFICIENCY 1215 Adulthood and a Large Number of Children and Adults with Protein C Mutations [6,13]
Haemophilia (2008), 14, 1214–1221 DOI: 10.1111/j.1365-2516.2008.01838.x ORIGINAL ARTICLE Protein C deficiency N. A. GOLDENBERG* and M. J. MANCO-JOHNSON* *Hemophilia & Thrombosis Center, Section of Hematology, Oncology, and Bone Marrow Transplantation, Department of Pediatrics, University of Colorado Denver and The ChildrenÕs Hospital, Aurora, CO; and Division of Hematology/ Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA Summary. Severe protein C deficiency (i.e. protein C ment of acute thrombotic events in severe protein C ) activity <1 IU dL 1) is a rare autosomal recessive deficiency typically requires replacement with pro- disorder that usually presents in the neonatal period tein C concentrate while maintaining therapeutic with purpura fulminans (PF) and severe disseminated anticoagulation; protein C replacement is also used intravascular coagulation (DIC), often with concom- for prevention of these complications around sur- itant venous thromboembolism (VTE). Recurrent gery. Long-term management in severe protein C thrombotic episodes (PF, DIC, or VTE) are common. deficiency involves anticoagulation with or without a Homozygotes and compound heterozygotes often protein C replacement regimen. Although many possess a similar phenotype of severe protein C patients with severe protein C deficiency are born deficiency. Mild (i.e. simple heterozygous) protein C with evidence of in utero thrombosis and experience deficiency, by contrast, is often asymptomatic but multiple further events, intensive treatment and may involve recurrent VTE episodes, most often monitoring can enable these individuals to thrive. triggered by clinical risk factors. The coagulopathy in Further research is needed to better delineate optimal protein C deficiency is caused by impaired inactiva- preventive and therapeutic strategies. -
Innate Immunity: the Inside Story on Complement Activation
RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis. -
A Family with Complement Factor D Deficiency
A family with complement factor D deficiency Douwe H. Biesma,1 André J. Hannema,2 Heleen van Velzen-Blad,3 Leontine Mulder,3 Rob van Zwieten,2 Irma Kluijt,4 and Dirk Roos2,5 1Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands 2Central Laboratory of the Netherlands Blood Transfusion Service, Amsterdam, The Netherlands 3Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands 4Department of Clinical Genetics, and 5Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Address correspondence to: Douwe H. Biesma, Department of Internal Medicine, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands. Phone: 31-30-6099111; Fax: 31-30-6056357; E-mail: [email protected]. Received for publication December 15, 2000, and accepted in revised form June 11, 2001. A complement factor D deficiency was found in a young woman who had experienced a serious Neis- seria meningitidis infection, in a deceased family member with a history of meningitis, and in three rel- atives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified fac- tor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. -
Targeting of Mannan-Binding Lectin-Associated Serine Protease-2 Confers Protection from Myocardial and Gastrointestinal Ischemia/Reperfusion Injury
Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury Wilhelm J. Schwaeblea,1, Nicholas J. Lyncha, James E. Clarkb, Michael Marberb, Nilesh J. Samanic, Youssif Mohammed Alia,d, Thomas Dudlere, Brian Parente, Karl Lhottaf, Russell Wallisa, Conrad A. Farrarg, Steven Sacksg, Haekyung Leeh, Ming Zhangh, Daisuke Iwakii, Minoru Takahashii, Teizo Fujitai, Clark E. Tedforde, and Cordula M. Stovera Departments of aInfection, Immunity, and Inflammation and cCardiovascular Sciences, University of Leicester, Leicester LE1 9HN, United Kingdom; bBritish Heart Foundation Centre and gMedical Research Council Centre for Transplantation and National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London SE1 9RT, United Kingdom; dFaculty of Pharmacy, Department of Microbiology, University of Mansoura, Mansoura 35516, Egypt; eOmeros Corporation, Seattle, WA 98101; fLandeskrankenhaus Feldkirch, 6807 Feldkirch, Austria; hDepartment of Anesthesiology, State University of New York-Downstate Medical Center, New York, NY 11203; and iDepartment of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011) Complement research experienced a renaissance with the discovery aberrant glycosylation