Sevuparin blocks sickle blood cell adhesion and sickle-leucocyte rolling on immobilized L-selectin in a dosedependent manner

Sevuparin blocks sickle blood cell adhesion and sickle-leucocyte rolling on immobilized L-selectin in a dosedependent manner

Publications, Adhesion, Dynamic Adhesion, VCAM-1, L-selectin

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British Journal of Haematology

Jennell White, Maria Lindgren, Ke Liu, Xiufeng Gao, Lena Jendeberg, Patrick Hines

First published: 16 May 2018

Adhesion of sickle red blood cells (SSRBC) to the vascular endothelium may initiate and propagate vascular obstruction in sickle cell disease (SCD) (Hoover et al, 1979; Hebbel et al, 1980). Hebbel et al (1980) were the first to report a correlation between erythrocyte adherence and disease severity. Subsequent studies demonstrated that the pathological adhesion of SSRBCs involves red cell receptors, adhesive bridging proteins and endothelial receptors (Joneckis et al, 1993; Swerlick et al, 1993; Udani et al, 1998; Hillery et al, 2000). These complex and multimodal mechanisms of SSRBC adhesion may require a multi‐targeted approach to achieve the best clinical outcome.

Sevuparin is a new drug candidate that is chemically derived from heparin and in which most of the anticoagulant activity has been removed while retaining the anti‐adhesive effects. Sevuparin is currently in Phase 2 clinical studies for acute treatment of vaso‐occlusive crisis (VOC) in SCD (NCT02515838). Heparins exhibit blockade of P‐selectin‐mediated adhesion. Selectins contribute to both SSRBC and neutrophil adhesion (PMN) in vitro and in SCD mouse models. Sickle mouse models lacking both P‐ and E‐selectins are relatively resistant to tumour necrosis factor‐alpha (TNFa)‐induced vaso‐occlusion. In vitroand in vivo studies with sevuparin have shown potent anti‐adhesive effects with a multimodal mechanism of action (Telen et al, 2016). In this study, a standardized flow adhesion assay was used to evaluate the effects of sevuparin on the adhesion of sickle whole blood to cultured endothelial cells and vascular cell adhesion molecule‐1 (VCAM‐1), and sickle‐leucocyte rolling adhesion on L‐selectin.

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