: Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide. Acute vaso-occlusive crisis is the main cause of hospitalization in patients with SCD. There is growing evidence that inflammatory vasculopathy plays a key role in both acute and chronic SCD-related clinical manifestations. In a humanized mouse model of SCD, we found an increase of von Willebrand factor activity and a reduction in the ratio of a disintegrin and metalloproteinase with thrombospondin type 1 motif, number 13 (ADAMTS13) to von Willebrand factor activity similar to that observed in the human counterpart. Recombinant ADAMTS13 was administered to humanized SCD mice before they were subjected to hypoxia/reoxygenation (H/R) stress as a model of vaso-occlusive crisis. In SCD mice, recombinant ADAMTS13 reduced H/R-induced hemolysis and systemic and local inflammation in lungs and kidneys. It also diminished H/R-induced worsening of inflammatory vasculopathy, reducing local nitric oxidase synthase expression. Collectively, our data provide for the firsttime evidence that pharmacological treatment with recombinant ADAMTS13 (TAK-755) diminished H/R-induced sickle cell-related organ damage. Thus, recombinant ADAMTS13 might be considered as a potential effective disease-modifying treatment option for sickle cell-related acute events.

Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease / Rossato, P.; Federti, E.; Matte, A.; Glantschnig, H.; Canneva, F.; Schuster, M.; Coulibaly, S.; Schrenk, G.; Voelkel, D.; Dockal, M.; Plaimauer, B.; Andolfo, I.; Iolascon, A.; Rottensteiner, H.; Gritsch, H.; Scheiflinger, F.; Hoellriegl, W.; De Franceschi, L.. - In: HAEMATOLOGICA. - ISSN 1592-8721. - 107:11(2022), pp. 2650-2660. [10.3324/haematol.2021.280233]

Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease

Andolfo I.;Iolascon A.;
2022

Abstract

: Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide. Acute vaso-occlusive crisis is the main cause of hospitalization in patients with SCD. There is growing evidence that inflammatory vasculopathy plays a key role in both acute and chronic SCD-related clinical manifestations. In a humanized mouse model of SCD, we found an increase of von Willebrand factor activity and a reduction in the ratio of a disintegrin and metalloproteinase with thrombospondin type 1 motif, number 13 (ADAMTS13) to von Willebrand factor activity similar to that observed in the human counterpart. Recombinant ADAMTS13 was administered to humanized SCD mice before they were subjected to hypoxia/reoxygenation (H/R) stress as a model of vaso-occlusive crisis. In SCD mice, recombinant ADAMTS13 reduced H/R-induced hemolysis and systemic and local inflammation in lungs and kidneys. It also diminished H/R-induced worsening of inflammatory vasculopathy, reducing local nitric oxidase synthase expression. Collectively, our data provide for the firsttime evidence that pharmacological treatment with recombinant ADAMTS13 (TAK-755) diminished H/R-induced sickle cell-related organ damage. Thus, recombinant ADAMTS13 might be considered as a potential effective disease-modifying treatment option for sickle cell-related acute events.
2022
Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease / Rossato, P.; Federti, E.; Matte, A.; Glantschnig, H.; Canneva, F.; Schuster, M.; Coulibaly, S.; Schrenk, G.; Voelkel, D.; Dockal, M.; Plaimauer, B.; Andolfo, I.; Iolascon, A.; Rottensteiner, H.; Gritsch, H.; Scheiflinger, F.; Hoellriegl, W.; De Franceschi, L.. - In: HAEMATOLOGICA. - ISSN 1592-8721. - 107:11(2022), pp. 2650-2660. [10.3324/haematol.2021.280233]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/914506
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