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      Inibição e reversão da agregação plaquetária de eqüinos in vitro com o uso de ketoprofeno, fenilbutazona e flunixim meglumine Translated title: In vitro inibition and reversion of equine platelet aggregation using ketoprophen, phenylbutazone and flunixin meglumin

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          Abstract

          Como são várias as enfermidades e os distúrbios que induzem à hipercoagulabilidade e à pré-ativação de plaquetas em eqüinos. A atividade de medicamentos utilizados para controle dessas enfermidades sobre a agregação de plaquetas pode, não apenas servir para avaliar sua evolução, como também a resposta terapêutica. Com o objetivo de avaliar a prevenção e a reversão da agregação plaquetária de eqüinos in vitro foram utilizados os antiinflamatórios não esteroidais (AINES): ketoprofeno, fenilbutazona e flunixim meglumine. A comparação demonstrou que a fenilbutazona e o ketoprofeno previnem a agregação de plaquetas de eqüinos induzida pelo ADP, de forma mais eficaz do que o flunixim-meglumine e, superior ao fragmento monoclonal de anticorpo Reopro, sendo semelhante a dos bloqueadores de receptores de membrana Ro-438857 e RGDS. Quanto a reverão da agregação plaquetária tanto a fenilbutazona quanto o ketoprofeno demonstraram efeitos dose-dependente.

          Translated abstract

          Several diseases may lead to platelet pre-activation and hypercoagulability states in horses. The activity of many drugs against platelet aggregation may, not only contribute to the evaluation of a disease but also its response to the therapy. With the aim to study in vitro prevention and reversion of platelet aggregation, the non steroidal anti-inflammatory drug (NSAID): ketoprophen, phenylbutazone and flunixin-meglumin were evaluated. The comparison demonstrated that phenylbutazone and ketoprophen prevented platelet aggregation induced by ADP better than flunixin-meglumin, in a superior manner to the monoclonal antibody Reopro, and in a better way than the membrane receptor blockers Ro-438857 and RGDS. The reversion of platelet aggregation demonstrated that even phenylbutazone or ketoprophen have a dose-dependent effect.

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          Most cited references23

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          Evaluation of platelet activation and platelet-neutrophil aggregates in ponies with alimentary laminitis.

          To determine whether platelets are hyperaggregable or form platelet-neutrophil aggregates during the prodromal stages of acute laminitis of ponies.
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            Histophysiology of the circulating platelet.

            The role of platelets in hemostasis and thrombosis has been well established since Eberth's and Schimmelbusch's pioneering intravital microscopic experiments. A century ago the distinct features of the circulating "smooth disc" and the activated "spiny sphere" were described. Since then the underlying cell-biological processes transforming a harmless floating platelet into a sticky corpuscle, ready to release its stores of thrombogenic and atherogenic substances have been unveiled. However, its life-threatening capabilities have evolved from the necessity of preventing equally dangerous blood losses from a pressurized circulation system. As circulation depends on the liquid state of blood, the platelets and the molecules of the plasmatic coagulation system must circulate in an inactive state, to become activated at the site of "demand" to transform the liquid into a solid hemostatic plug. As in nucleated cells the plasma membrane, made up of a phospholipid bilayer with integrated glycoproteins, is the structure signalling environmental information to the platelet interior. Many of the receptors for stimulatory or inhibitory mediators elicit a cell-biological response via G-proteins and subsequent Ca2+ mobilization by IP3, or stimulation/inhibition of adenylate cyclase followed by changes in cytoplasmic levels of cyclic AMP. The supposed intracellular Ca2+ store of the platelets, the dense tubular system, also appears as the site of Ca2(+)-activated prostaglandin synthesis. Raised cytoplasmic Ca2+ levels promote the polymerization of G-actin to F-actin involved in the extension of pseudopodia in the course of "external shape change." Ca2(+)-activated myosin light-chain kinase phosphorylates myosin which becomes associated with F-actin, with the resulting acto-myosin complex providing the contractile force for "internal shape change," i.e., the centralization of organelles and for clot retraction later in hemostasis. More than by the three-dimensional actin cytoskeleton proper, the discoid shape typical of the nonstimulated platelet appears to be secured by a two-dimensional membrane skeleton of actin filaments anchored to membrane glycoproteins via actin-binding protein or spectrin and ankyrin. Although the microtubule coil has been confirmed as the main determinant of the mechanical stiffness of the platelet with biophysical techniques, its hitherto assumed role for the maintenance of the disc shape no longer appears tenable. The morphological phenomenon of the shape change comprises an alteration of membrane glycoproteins resulting in binding of "adhesive" molecules like fibrinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Platelet Adhesion and Aggregation without Endothelial Denudation or Exposure of Basal Lamina and/or Collagen

              In vivo microvascular studies and postmortem studies of large and small blood vessels in a variety of species and vascular beds show that platelet adhesion and aggregation can occur over endothelium that is not denuded; the basal lamina and collagen need not be exposed. Moreover, evidence suggests that, at least in arterioles, locally adherent degranulating platelets can actually produce disruption and denudation of endothelial cells. Therefore, one should not assume, at least in small vessels, that observed sites of denudation were the cause rather than the result of adhesion/aggregation. All of this evidence should encourage a greatly increased emphasis on causes of adhesion/aggregation that do not depend upon collagen and/or collagen-bound von Willebrand factor (vWF). This emphasis does not deny the importance of collagen or collagen-bound vWF as the trigger for adhesion/aggregation when such exposure occurs. However, the emphasis on a structurally intact endothelial surface does lead to the corollary caution: even when endothelium is interrupted and potential triggers of adhesion/aggregation are exposed, this does not mean that these substances were, in fact, the cause of the locally observed adhesion/ aggregation. Local exposure of key endothelial cell adhesion molecules such as PEC AM may contribute to the adhesion/aggregation of platelets over structurally intact but injured endothelium. Adhesion/aggregation over injured but intact endothelium can also be modified by maneuvers that alter the local production of antiplatelet paracrine substances like endothelium-derived relaxing factor/nitric oxide. This supports the hypothesis that local decrements in the release of antiplatelet paracrine substances from perturbed but structurally intact endothelium leads to local adhesion/aggregation especially of platelets activated by a preexisting pathology. Coronary artery disease, ischemic stroke and diabetes are examples of diseases associated with both hyperaggregable platelets and with impaired endothelial synthesis/release of antiplatelet paracrine mediators. In addition, repetitive stereotypic symptoms in transient ischemic attacks may be related to repetitive and increasing damage to endothelium produced by successive episodes of platelet adhesion/ aggregation/degranulation at the same sites.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                pvb
                Pesquisa Veterinária Brasileira
                Pesq. Vet. Bras.
                Colégio Brasileiro de Patologia Animal - CBPA (Rio de Janeiro )
                1678-5150
                October 2009
                : 29
                : 10
                : 803-808
                Affiliations
                [1 ] Universidade Federal de Minas Gerais Brasil
                [2 ] Ludwig-Maximilians-Universität München Alemanha
                [3 ] Universidade Federal de Minas Gerais Brasil
                [4 ] Universidade Federal do Pará Brazil
                Article
                S0100-736X2009001000005
                10.1590/S0100-736X2009001000005
                4463e42a-3735-4d6c-89ba-5d922d20e62f

                http://creativecommons.org/licenses/by/4.0/

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                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0100-736X&lng=en
                Categories
                VETERINARY SCIENCES

                General veterinary medicine
                Aggregometry,ADP,Reopro,RGDS,Ro-438857,NSAId,Agregometria,AINES
                General veterinary medicine
                Aggregometry, ADP, Reopro, RGDS, Ro-438857, NSAId, Agregometria, AINES

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