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

Summary 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 ‐ RBC s) 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 .