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      Heparin 2.0: A New Approach to the Infection Crisis

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          Abstract

          In April 2020, the US Food and Drug Administration granted emergency use authorization for certain medical devices to be used in patients with coronavirus disease 2019 (CO­VID-19). This included extracorporeal blood purification devices. This narrative review will give a brief overview regarding some of the extracorporeal devices that could be used to treat COVID-19 patients, including the Seraph® 100 Microbind® Affinity Blood Filter, produced by ExThera Medical (Martinez, CA, USA), first licensed in the European Economic Area in 2019. The Seraph® 100 contains ultrahigh molecular weight polyethylene beads with end point-attached heparin and is approved for the reduction of pathogens from the bloodstream either as a single agent or as an adjunct to conventional anti-infective agents. Bacteria, viruses, fungi, and toxins have been shown to bind to the immobilized heparin in a similar way to the interaction with heparan sulfate on the cell surface. This binding is nonreversible and as such, the pathogens are removed from the bloodstream. In this review, we describe the pathophysiological basis and rationale for using heparin for pathogen removal from the blood as well as exploring the technology behind the adaptation of heparin to deprive it of its systemic anticoagulant activity. In addition, we summarize the in vitro data as well as the available preclinical testing and published clinical reports. Finally, we discuss the enormous potential of this technology in an era of increasing antibiotic resistance and high mortality associated with sepsis and consider the application of this as a possible treatment option for COVID-19.

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          Most cited references 18

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          Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans.

          Contrary to many other viruses, the initial steps of the hepatitis B virus (HBV) infection, including attachment to hepatocytes, specific receptor interactions, and membrane fusion, are unsolved. Using HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cell-surface-associated heparan sulfate proteoglycans. Binding to GAGs requires the integrity of the pre-S domain as a part of the large (L-) viral envelope protein. HBV infection was abrogated by incubation of virions with heparin, but not the structurally related GAGs chondroitin sulfate A, B, and C. Infection was also abolished by suramin, a known inhibitor of duck hepatitis B virus infection or highly sulfated dextran sulfate. Polycationic substances such as poly-L-lysine, polybrene, and protamine also prevented infection, however, by addressing cellular components. Enzymatic removal of defined acidic carbohydrate structures from the cell surface using heparinase I/III or the obstruction of GAG synthesis by sodium chlorate inhibited HBV infection of HepaRG cells and, moreover, led to a reduction of HBV cell surface binding sites. The biochemical analysis showed selective binding of L-protein-enriched viral particles (virions or filaments) to heparin. GAG-dependent binding of HBV was improved by polyethylene glycol, a substance that specifically enhances HBV infection. HBV infection requires the initial attachment to the carbohydrate side chains of hepatocyte-associated heparan sulfate proteoglycans as attachment receptors. This interaction initializes the multistep entry process of HBV and cannot be bypassed by alternative routes.
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            Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis.

            Severe sepsis and septic shock are the primary causes of multiple organ dysfunction syndrome (MODS), which is the most frequent cause of death in intensive care unit patients. Many water-soluble mediators with pro- and anti-inflammatory action such as TNF, IL-6, IL-8, and IL-10 play a strategic role in septic syndrome. In intensive care medicine, blocking any one mediator has not led to a measurable outcome improvement in patients with sepsis. CRRT is a continuously acting therapy, which removes in a nonselective way pro- and anti-inflammatory mediators; "the peak concentration hypothesis" is the concept of cutting peaks of soluble mediators through continuous hemofiltration. Furthermore, there is evidence of increased efficacy of high-volume hemofiltration compared to conventional CVVH, and other blood purification techniques that utilize large-pore membranes or sorbent plasmafiltration are conceptually interesting.
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              Microbial adherence to and invasion through proteoglycans.

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                Author and article information

                Journal
                Blood Purif
                Blood Purif
                BPU
                Blood Purification
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                0253-5068
                1421-9735
                2 July 2020
                : 1-7
                Affiliations
                aMedical Clinic V, Nephrology | Rheumatology | Blood Purification, Academic Teaching Hospital Braunschweig, Braunschweig, Germany
                bMicrobial Proteomics, Helmholtz Centre for Infection Research, Braunschweig, Germany
                cIntensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom
                dDepartment of Clinical & Experimental Medicine, School of Biosciences & Medicine, University of Surrey, Guildford, United Kingdom
                Author notes
                *Jan T. Kielstein, Academic Teaching Hospital Braunschweig, Medical Clinic V Nephrology | Rheumatology | Blood Purification, Salzdahlumer Straße 90, DE–38126 Braunschweig (Germany), j.kielstein@ 123456klinikum-braunschweig.de
                Article
                bpu-0001
                10.1159/000508647
                7445380
                32615569
                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                Page count
                Figures: 4, References: 34, Pages: 7
                Categories
                Review

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