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      Platelet Function and Therapeutic Applications in Dogs: Current Status and Future Prospects

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          Abstract

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          Platelets, small blood cells produced from megakaryocytes mainly in the bone marrow, are implicated not only in hemostasis, but also in different physiological and pathophysiological processes. This paper reviews canine platelet structure and functions, including an accurate description of the numerous surface receptors involved in the mechanisms of platelet adhesion and aggregation. In addition, we describe the most important canine platelet disorders that can affect platelet numbers (thrombocytopenias and thrombocytosis) or platelet function (thrombopathias). Platelet-related tests are vital in the analysis of primary hemostatic disorders and for this reason, we also discuss the efficacy of various tests in the diagnosis of canine platelet disorders. Finally, innovative therapeutic approaches based on the use of platelets and their derivatives for the treatment of various canine diseases such as inflammatory conditions (tendinitis and osteoarthritis) and for wound healing and tissue repair are reported.

          Abstract

          Significant progress has been made in the functional characterization of canine platelets in the last two decades. The role of canine platelets in hemostasis includes their adhesion to the subendothelium, activation, and aggregation, leading to primary clot formation at the site of injury. Studies on canine platelet function and advancements in laboratory testing have improved the diagnosis and understanding of platelet-related disorders as well as the knowledge of the mechanisms behind these diseases. This review focuses on the most recent discoveries in canine platelet structure, function, and disorders; and discusses the efficacy of various tests in the diagnosis of platelet-related disorders. With the relatively recent discovery of angiogenetic and reparative effects of growth factors found in platelets, this review also summarizes the use of canine platelet-rich plasma (PRP) alone or in association with stem cells in regenerative therapy. The characterization of proteomic and lipidomic profiles and development of platelet gene therapy in veterinary species are areas of future study with potential for major therapeutic benefits.

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          Most cited references178

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          Platelet-rich plasma: a milieu of bioactive factors.

          Platelet concentrates such as platelet-rich plasma (PRP) have gained popularity in sports medicine and orthopaedics to promote accelerated physiologic healing and return to function. Each PRP product varies depending on patient factors and the system used to generate it. Blood from some patients may fail to make PRP, and most clinicians use PRP without performing cell counts on either the blood or the preparation to confirm that the solution is truly PRP. Components in this milieu have bioactive functions that affect musculoskeletal tissue regeneration and healing. Platelets are activated by collagen or other molecules and release growth factors from alpha granules. Additional substances are released from dense bodies and lysosomes. Soluble proteins also present in PRP function in hemostasis, whereas others serve as biomarkers of musculoskeletal injury. Electrolytes and soluble plasma hormones are required for cellular signaling and regulation. Leukocytes and erythrocytes are present in PRP and function in inflammation, immunity, and additional cellular signaling pathways. This article supports the emerging paradigm that more than just platelets are playing a role in clinical responses to PRP. Depending on the specific constituents of a PRP preparation, the clinical use can theoretically be matched to the pathology being treated in an effort to improve clinical efficacy. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.
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            The platelet release reaction: granules' constituents, secretion and functions.

            Although anucleated, blood platelets are highly organized cells rich in different types of organelles. Three specific granule populations store different types of constituents, some of which are at high concentrations. Platelets thus transport some specific compounds through the whole body. During circulation, platelets are reactive to various stimuli and release the materials stored in the specific granules. This 'release reaction' is an important step of primary haemostasis. Energy and messengers required for platelet reactivity are provided by mitochondria and the dense tubular system. Each granule population has specific properties concerning both the structure and the role played by the released constituents. Dense granules contain small non-protein molecules that are secreted to recruit other platelets. alpha-Granules contain large adhesive and healing proteins. Lysosomes contain hydrolases able to eliminate the circulating platelet aggregate. The extrusion of storage granules' content to the platelet's environment occurs according to regulated secretion events: movements of granules, apposition and fusion of granule and plasma membranes. Typical platelet disorders resulting from a storage granule abnormality are referred to as a storage pool defect and are characterized by a prolonged bleeding time.
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              Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells.

              Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.
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                Author and article information

                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                25 January 2020
                February 2020
                : 10
                : 2
                : 201
                Affiliations
                [1 ]Department of Veterinary Medicine and Animal Productions, Division of Internal Medicine, University of Naples Federico II, Via Delpino, 1, 80137 Naples, Italy; lcortese@ 123456unina.it
                [2 ]Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; chrispw@ 123456auburn.edu
                [3 ]Department of Advanced Biomedical Sciences, University of Naples “Federico II”, 80131 Naples, Italy
                [4 ]Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Naples, Italy
                Author notes
                [* ]Correspondence: alpelaga@ 123456unina.it
                Author information
                https://orcid.org/0000-0002-1133-4300
                Article
                animals-10-00201
                10.3390/ani10020201
                7071006
                31991713
                8107384a-237c-465e-b7d0-b88b7cbba17b
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 January 2020
                : 22 January 2020
                Categories
                Review

                dog,platelets,physiology,therapy,regenerative medicine
                dog, platelets, physiology, therapy, regenerative medicine

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