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      Novel mouse hemostasis model for real-time determination of bleeding time and hemostatic plug composition

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          Most cited references26

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          The final steps of integrin activation: the end game.

          Cell-directed changes in the ligand-binding affinity ('activation') of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction, thereby contributing to embryonic development and diseases such as atherothrombosis and cancer. Integrin activation comprises triggering events, intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators, which changes an integrin's affinity for its ligands. The first two events involve diverse interacting signalling pathways, whereas the final steps are immediately proximal to integrins, thus enabling integrin-focused therapeutic strategies. Recent progress provides insight into the structure of integrin transmembrane domains, and reveals how the final steps of integrin activation are mediated by integrin-binding proteins such as talins and kindlins.
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            Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow.

            We have used confocal videomicroscopy in real time to delineate the adhesive interactions supporting platelet thrombus formation on biologically relevant surfaces. Type I collagen fibrils exposed to flowing blood adsorb von Willebrand factor (vWF), to which platelets become initially tethered with continuous surface translocation mediated by the membrane glycoprotein Ib alpha. This step is essential at high wall shear rates to allow subsequent irreversible adhesion and thrombus growth mediated by the integrins alpha2beta1 and alpha(IIb)beta3. On subendothelial matrix, endogenous vWF and adsorbed plasma vWF synergistically initiate platelet recruitment, and alpha2beta1 remains key along with alpha(IIb)beta3 for normal thrombus development at all but low shear rates. Thus, hemodynamic forces and substrate characteristics define the platelet adhesion pathways leading to thrombogenesis.
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              Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A.

              Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.
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                Author and article information

                Journal
                Journal of Thrombosis and Haemostasis
                J Thromb Haemost
                Wiley
                15387933
                March 2015
                March 2015
                January 09 2015
                : 13
                : 3
                : 417-425
                Affiliations
                [1 ]McAllister Heart Institute; University of North Carolina; Chapel Hill NC USA
                [2 ]Department of Pediatrics; EMORY University; Atlanta GA USA
                [3 ]Department of Medicine; University of North Carolina; Chapel Hill NC USA
                [4 ]Department of Biochemistry and Biophysics; University of North Carolina; Chapel Hill NC USA
                Article
                10.1111/jth.12802
                a7cb5d81-b85b-4630-b472-f068bcef952d
                © 2015

                http://doi.wiley.com/10.1002/tdm_license_1.1

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