Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion.
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.
['Telen|Marilyn J|MJ|', 'Batchvarova|Milena|M|', 'Shan|Siqing|S|', 'Bovee-Geurts|Petra H|PH|', 'Zennadi|Rahima|R|', 'Leitgeb|Anna|A|', 'Brock|Roland|R|', 'Lindgren|Maria|M|']
D000755:Anemia, Sickle Cell D000818:Animals D001157:Arterial Occlusive Diseases D002448:Cell Adhesion D002478:Cells, Cultured D042783:Endothelial Cells D004912:Erythrocytes D006493:Heparin D006495:Heparin, Low-Molecular-Weight D006801:Humans D051379:Mice D011485:Protein Binding D000078222:Tinzaparin
vaso-occlusion sickle cell disease heparinoids adhesion receptors cell adhesion