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      The molecular basis for the prothrombotic state in sickle cell disease

      research-article
      1 , 1 , 2
      Haematologica
      Fondazione Ferrata Storti

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          Abstract

          The genetic and molecular basis of sickle cell disease (SCD) has long been characterized but the pathophysiological basis has not been entirely defined. How a red cell hemolytic disorder initiates inflammation, endothelial dysfunction, coagulation activation, and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a history of VTE. Here, we provide an in-depth review of the molecular basis for the prothrombotic state in SCD, specifically highlighting emerging evidence for activation of overlapping inflammation and coagulation pathways that predispose to venous thromboembolism. We share perspectives in managing venous thrombosis in SCD, highlighting innovative therapies with the potential to influence the clinical course of disease and reduce thrombotic risk, while maintaining an acceptable safety profile.

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          Most cited references119

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          Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report.

          We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics.
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            Mechanisms of thrombus formation.

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              Pathophysiology of Sickle Cell Disease

              Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: ( a) hemoglobin S polymerization, ( b) impaired biorheology and increased adhesion-mediated vaso-occlusion, ( c) hemolysis-mediated endothelial dysfunction, and ( d) concerted activation of sterile inflammation (Toll-like receptor 4– and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                HAEMA
                Haematologica
                Fondazione Ferrata Storti
                0390-6078
                1592-8721
                01 October 2020
                01 October 2020
                : 105
                : 10
                : 239350
                Affiliations
                [1 ]Laboratory of Sickle Thrombosis and Vascular Biology, National Heart, Lung, and Blood Institute , NIH, Bethesda
                [2 ]Division of Hematology, Department of Medicine, Johns Hopkins University , Baltimore, MD, USA
                Author notes
                Article
                10.3324/haematol.2019.239350
                7556662
                33054077
                1d6d45a6-9b7c-4a75-a19a-f05c83e96416
                Copyright© 2020 Ferrata Storti Foundation

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                History
                : 06 April 2020
                : 22 July 2020
                : 13 August 2020
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 137, Pages: 12
                Categories
                Review Article

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