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      Dual roles for hepatic lectin receptors in the clearance of chilled platelets

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          Abstract

          Chilling rapidly (<4 h) clusters Glycoprotein - (GP)Ib receptors on blood platelets, and ß2-integrins of hepatic macrophages bind ßGlcNAc residues in the clusters leading to rapid clearance of acutely chilled platelets following transfusion. Although capping the ßGlcNAc moieties by galactosylation prevents clearance, this strategy is ineffective after prolonged (>24 h) refrigeration. We report here that prolonged refrigeration increases the density/concentration of exposed galactose residues such that hepatocytes become increasingly involved in the removal of platelets using their Ashwell-Morell receptors. Macrophages always rapidly remove a large fraction of transfused platelets (~40%). With platelet cooling, hepatocyte-dependent clearance further diminishes their recoveries following transfusion.

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          Actin-binding protein requirement for cortical stability and efficient locomotion.

          Three unrelated tumor cell lines derived from human malignant melanomas lack actin-binding protein (ABP), which cross-links actin filaments in vitro and connects these filaments to plasma membrane glycoproteins. The ABP-deficient cells have impaired locomotion and display circumferential blebbing of the plasma membrane. Expression of ABP in one of the lines after transfection restored translocational motility and reduced membrane blebbing. These findings establish that ABP functions to stabilize cortical actin in vivo and is required for efficient cell locomotion.
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            The Ashwell receptor mitigates the lethal coagulopathy of sepsis.

            The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.
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              The clearance mechanism of chilled blood platelets.

              Platelet transfusion is a very common lifesaving medical procedure. Not widely known is the fact that platelets, unlike other blood cells, rapidly leave the circulation if refrigerated prior to transfusion. This peculiarity requires blood services to store platelets at room temperature, limiting platelet supplies for clinical needs. Here, we describe the mechanism of this clearance system, a longstanding mystery. Chilling platelets clusters their von Willebrand (vWf) receptors, eliciting recognition of mouse and human platelets by hepatic macrophage complement type 3 (CR3) receptors. CR3-expressing but not CR3-deficient mice exposed to cold rapidly decrease platelet counts. Cooling primes platelets for activation. We propose that platelets are thermosensors, primed at peripheral sites where most injuries occurred throughout evolution. Clearance prevents pathologic thrombosis by primed platelets. Chilled platelets bind vWf and function normally in vitro and ex vivo after transfusion into CR3-deficient mice. Therefore, GPIb modification might permit cold platelet storage.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                6 May 2015
                27 September 2009
                November 2009
                12 May 2015
                : 15
                : 11
                : 1273-1280
                Affiliations
                [1 ]Division of Translational Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston 02115, USA
                [2 ]Department of Clinical Chemistry and Transfusion Medicine, Institute of Laboratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
                [3 ]The Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
                Author notes
                [* ]To whom correspondence should be addressed: Karin Hoffmeister, Division of Translational Medicine, Brigham and Women’s Hospital, 1 Blackfan Circle, KARP 6, Boston, MA 02115; khoffmeister@ 123456rics.bwh.harvard.edu
                Article
                NIHMS144497
                10.1038/nm.2030
                4428152
                19783995
                736c3aed-4910-4999-b0ff-bd6bb9edccfd
                History
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                Medicine
                Medicine

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