Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Telen, MJ; Batchvarova, M; Shan, S; Bovee-Geurts, PH; Zennadi, R; Leitgeb, A; Brock, R; Lindgren, M

Published Date

  • December 2016

Published In

Volume / Issue

  • 175 / 5

Start / End Page

  • 935 - 948

PubMed ID

  • 27549988

Pubmed Central ID

  • 27549988

Electronic International Standard Serial Number (EISSN)

  • 1365-2141

Digital Object Identifier (DOI)

  • 10.1111/bjh.14303

Language

  • eng

Conference Location

  • England