Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease

Abstract

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)–induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

Altered VWF:ADAMTS13 homeostasis is a target for therapeutic intervention in sickle cell disease

“…Further support for the experiments conducted by Shi et al. ( 5 ) implicating the delicate balance between VWF and ADAMTS13 in VOE was provided by Rossato et al. ( 6 ).…”

“…Together, the experimental data from Shi et al. ( 5 ) and Rossato et al. ( 6 ) demonstrate that endothelial-VWF knockout and rADAMTS13 infusion prior to experimental VOE, prevent VOE in sickle cell mouse models.…”

“…To address this therapeutic gap in preventing VOEs, Shi et al. ( 5 ) examined the role of the Von Willebrand factor (VWF) in sickle cell mice with VOE and the effect of ADAMTS13, a VWF-cleaving protease, on reducing inflammation, vaso-occlusion, and organ damage in a mouse model of sickle cell VOE. The possibility of a fourth agent that may provide multimodal synergistic therapy with a completely different mechanism of action is a potentially critical breakthrough.…”

“…Shi et al. ( 5 ) used intraperitoneal injection of tumor necrosis factor (TNF) to induce VOE in HbSS (Townes) mice. Recapitulating VOE in individuals with SCD, the experimental VOE was associated with increased plasma VWF levels as well as inflammatory infiltrates and vascular occlusions in multiple tissues.…”

“…To establish that VWF contributes directly to the pathogenesis of VOE, Shi et al. ( 5 ) generated HbSS mice lacking endothelial VWF and showed that these mice have reduced inflammatory infiltrates and vaso-occlusions in response to TNF challenge. Finally, the group pretreated HbSS mice with recombinant ADAMTS13 before TNF injection.…”