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      Accumulation of Tissue Factor into Developing Thrombi In Vivo Is Dependent upon Microparticle P-Selectin Glycoprotein Ligand 1 and Platelet P-Selectin

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          Abstract

          Using a laser-induced endothelial injury model, we examined thrombus formation in the microcirculation of wild-type and genetically altered mice by real-time in vivo microscopy to analyze this complex physiologic process in a system that includes the vessel wall, the presence of flowing blood, and the absence of anticoagulants. We observe P-selectin expression, tissue factor accumulation, and fibrin generation after platelet localization in the developing thrombus in arterioles of wild-type mice. However, mice lacking P-selectin glycoprotein ligand 1 (PSGL-1) or P-selectin, or wild-type mice infused with blocking P-selectin antibodies, developed platelet thrombi containing minimal tissue factor and fibrin. To explore the delivery of tissue factor into a developing thrombus, we identified monocyte-derived microparticles in human platelet–poor plasma that express tissue factor, PSGL-1, and CD14. Fluorescently labeled mouse microparticles infused into a recipient mouse localized within the developing thrombus, indicating that one pathway for the initiation of blood coagulation in vivo involves the accumulation of tissue factor– and PSGL-1–containing microparticles in the platelet thrombus expressing P-selectin. These monocyte-derived microparticles bind to activated platelets in an interaction mediated by platelet P-selectin and microparticle PSGL-1. We propose that PSGL-1 plays a role in blood coagulation in addition to its known role in leukocyte trafficking.

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          Most cited references 50

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          Selectins and their ligands: current concepts and controversies.

           G Kansas (1996)
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            The molecular basis of blood coagulation.

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              Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice.

              P selectin, expressed on surfaces of activated endothelial cells and platelets, is an adhesion receptor for leukocytes. We report that P selectin-deficient mice, generated by gene targeting in embryonic stem cells, exhibit a number of defects in leukocyte behavior, including elevated numbers of circulating neutrophils, virtually total absence of leukocyte rolling in mesenteric venules, and delayed recruitment of neutrophils to the peritoneal cavity upon experimentally induced inflammation. These results clearly demonstrate a role for P selectin in leukocyte interactions with the vessel wall and in the early steps of leukocyte recruitment at sites of inflammation. These mutant mice should prove useful in deciphering the contributions of P selectin in various inflammatory responses as well as in platelet functions.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                2 June 2003
                : 197
                : 11
                : 1585-1598
                Affiliations
                Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
                Author notes

                Address correspondence to Bruce Furie, Center for Hemostasis and Thrombosis Research, Research East 319, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-0620; Fax: 617-975-5505; E-mail: bfurie@ 123456caregroup.harvard.edu

                Article
                20021868
                10.1084/jem.20021868
                2193915
                12782720
                Copyright © 2003, The Rockefeller University Press
                Categories
                Article

                Medicine

                intravital microscopy, thrombosis, blood coagulation, fibrin, endothelium

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