title: Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion.
abstract: Sevuparin is a novel drug candidate in phase II development as a treatment for vaso-occlusive crises (VOC) in patients with sickle cell disease (SCD). As a heparin-derived polysaccharide, sevuparin has been designed to retain anti-adhesive properties, while the antithrombin-binding domains have been eliminated, substantially diminishing its anticoagulant activity. Here, we demonstrate that sevuparin inhibits the adhesion of human sickle red blood cells (SS-RBCs) to stimulated cultured endothelial cells in vitro. Importantly, sevuparin prevents vaso-occlusion and normalizes blood flow in an in vivo mouse model of SCD vaso-occlusion. Analyses by surface plasmon resonance (SPR) and fluorescence correlation spectroscopy (FCS) demonstrate that sevuparin binds to P- and L-selectins, thrombospondin, fibronectin and von Willebrand factor, all of which are thought to contribute to vaso-occlusion in SCD. Despite low anticoagulation activity, sevuparin has anti-adhesive efficacy similar to the low molecular weight heparin tinzaparin both in vitro and in vivo. These results suggest that the anti-adhesive properties rather than the anticoagulant effects of heparinoids are critical for the treatment of vaso-occlusion in SCD. Therefore, sevuparin is now being evaluated in SCD patients hospitalized for treatment of VOC.
authors.affiliation: Division of Hematology, Department of Medicine, Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.affiliation: Division of Hematology, Department of Medicine, Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Batchvarova
authors.affiliation: Division of Hematology, Department of Medicine, Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Shan
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Petra H
authors.initials: PH
authors.lastname: Bovee-Geurts
authors.affiliation: Division of Hematology, Department of Medicine, Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Rahima
authors.initials: R
authors.lastname: Zennadi
authors.affiliation: Dilaforette AB, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Leitgeb
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Brock
authors.affiliation: Dilaforette AB, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindgren
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D011485:Protein Binding; D000078222:Tinzaparin
chemical_list: D006495:Heparin, Low-Molecular-Weight; C000619443:sevuparin; D000078222:Tinzaparin; D006493:Heparin
keywords: adhesion receptors; cell adhesion; heparinoids; sickle cell disease; vaso-occlusion