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      Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease

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          Abstract

          Sickle cell disease (SCD) is a recessive genetic blood disorder exhibiting abnormal blood rheology. Polymerization of sickle hemoglobin, due to a point mutation in the β‐globin gene of hemoglobin, results in aberrantly adhesive and stiff red blood cells (RBCs). Hemolysis, abnormal RBC adhesion, and abnormal blood rheology together impair endothelial health in people with SCD, which leads to cumulative systemic complications. Here, we describe a microfluidic assay combined with a micro particle image velocimetry technique for the integrated in vitro assessment of whole blood viscosity (WBV) and RBC adhesion. We examined WBV and RBC adhesion to laminin (LN) in microscale flow in whole blood samples from 53 individuals with no hemoglobinopathies (HbAA, N = 10), hemoglobin SC disease (HbSC, N = 14), or homozygous SCD (HbSS, N = 29) with mean WBV of 4.50 cP, 4.08 cP, and 3.73 cP, respectively. We found that WBV correlated with RBC count and hematocrit in subjects with HbSC or HbSS. There was a significant inverse association between WBV and RBC adhesion under both normoxic and physiologically hypoxic (SpO 2 of 83%) tests, in which lower WBV associated with higher RBC adhesion to LN in subjects with HbSS. Low WBV has been found by others to associate with endothelial activation. Altered WBV and abnormal RBC adhesion may synergistically contribute to the endothelial damage and cumulative pathophysiology of SCD. These findings suggest that WBV and RBC adhesion may serve as clinically relevant biomarkers and endpoints in assessing emerging targeted and curative therapies in SCD.

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          Most cited references82

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          Sickle-cell disease.

          Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Sickle Cell Anemia, a Molecular Disease

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              A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease

              Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.
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                Author and article information

                Contributors
                umut@case.edu
                Journal
                Am J Hematol
                Am J Hematol
                10.1002/(ISSN)1096-8652
                AJH
                American Journal of Hematology
                John Wiley & Sons, Inc. (Hoboken, USA )
                0361-8609
                1096-8652
                10 August 2020
                November 2020
                : 95
                : 11 ( doiID: 10.1002/ajh.v95.11 )
                : 1246-1256
                Affiliations
                [ 1 ] Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland Ohio
                [ 2 ] Division of Hematology and Oncology, School of Medicine Case Western Reserve University Cleveland Ohio
                [ 3 ] Division of Hematology and Blood Research Center, Department of Medicine University of North Carolina Chapel Hill North Carolina
                [ 4 ] Department of Biomedical Engineering Case Western Reserve University Cleveland Ohio
                Author notes
                [*] [* ] Correspondence

                Umut A. Gurkan, Department of Mechanical and Aerospace Engineering, Department of Biomedical Engineering, Case Western Reserve University, Glennan 616B, 10900 Euclid Ave. Cleveland, OH 44106.

                Email: umut@ 123456case.edu

                Author information
                https://orcid.org/0000-0002-3034-5523
                https://orcid.org/0000-0002-0331-9960
                Article
                AJH25933
                10.1002/ajh.25933
                7689825
                32656816
                8c46c61a-7935-428c-83ff-ffb95ff58911
                © 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 01 July 2020
                : 07 July 2020
                : 08 July 2020
                Page count
                Figures: 4, Tables: 0, Pages: 11, Words: 9620
                Funding
                Funded by: Case Western Reserve University , open-funder-registry 10.13039/100008136;
                Funded by: The Cure Sickle Cell Initiative
                Funded by: University Hospitals , open-funder-registry 10.13039/100012324;
                Funded by: National Heart, Lung, and Blood Institute , open-funder-registry 10.13039/100000050;
                Award ID: OT2HL152643
                Award ID: R01HL133574
                Award ID: T32HL134622
                Award ID: U01HL117659
                Funded by: National Science Foundation , open-funder-registry 10.13039/100000001;
                Award ID: 1552782
                Award ID: 1706295
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                November 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.4 mode:remove_FC converted:26.11.2020

                Hematology
                Hematology

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