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J Thromb Haemost

Title:		"Treatment with recombinant ADAMTS13, alleviates hypoxia/reoxygenation-induced pathologies in a mouse model of human sickle cell disease"
Author(s):		Rossato P; Glantschnig H; Canneva F; Schuster M; Coulibaly S; Schrenk G; Voelkel D; Dockal M; Plaimauer B; Rottensteiner H; Gritsch H; Federti E; Matte A; De Franceschi L; Scheiflinger F; Hoellriegl W;
Address:		"Baxalta Innovations GmbH, Vienna, Austria. Baxalta Innovations GmbH, Vienna, Austria. Electronic address: gerald.schrenk@takeda.com. Department of Medicine, University of Verona, Verona, Italy; Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico GB Rossi, Verona, Italy"
Journal Title:		J Thromb Haemost
Year:		2023
Volume:		20221222
Issue:		2
Page Number:		269 - 275
DOI:		10.1016/j.jtha.2022.10.016
ISSN/ISBN:		1538-7836 (Electronic) 1538-7836 (Linking)
Abstract:		"BACKGROUND: Sickle cell disease (SCD) is an inherited red blood cell disorder with a causative substitution in the beta-globin gene that encodes beta-globin in hemoglobin. Furthermore, the ensuing vasculopathy in the microvasculature involves heightened endothelial cell adhesion, inflammation, and coagulopathy, all of which contribute to vaso-occlusive crisis (VOC) and the sequelae of SCD. In particular, dysregulation of the von Willebrand factor (VWF) and a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in human SCD pathology. OBJECTIVES: To investigate the beneficial potential of treatment with recombinant ADAMTS13 (rADAMTS13) to alleviate VOC. METHODS: Pharmacologic treatment with rADAMTS13 in vitro or in vivo was performed in a humanized mouse model of SCD that was exposed to hypoxia/reoxygenation stress as a model of VOC. Then, pharmacokinetic, pharmacodynamic, and behavioral analyses were performed. RESULTS: Administration of rADAMTS13 to SCD mice dose-dependently increased plasma ADAMTS13 activity, reduced VWF activity/antigen ratios, and reduced baseline hemolysis (free hemoglobin and total bilirubin) within 24 hours. rADAMTS13 was administered in SCD mice, followed by hypoxia/reoxygenation stress, and reduced VWF activity/antigen ratios in parallel to significantly (p < .01) improved recovery during the reoxygenation phase. Consistent with the results in SCD mice, we demonstrate in a human in vitro system that treatment with rADAMTS13 counteracts the inhibitory activity of hemoglobin on the VWF/ADAMTS13-axis. CONCLUSION: Collectively, our data provide evidence that relative ADAMTS13 insufficiency in SCD mice is corrected by pharmacologic treatment with rADAMTS13 and provides an effective disease-modifying approach in a human SCD mouse model"
Keywords:		"Humans Animals Mice von Willebrand Factor/metabolism *Volatile Organic Compounds *Anemia, Sickle Cell/drug therapy *Vascular Diseases Hemolysis ADAMTS13 Protein/genetics Adamts13 mouse model recombinant ADAMTS13 sickle cell disease vaso-occlusive crisis;"
Notes:		"MedlineRossato, Paolo Glantschnig, Helmut Canneva, Fabio Schuster, Maria Coulibaly, Sogue Schrenk, Gerald Voelkel, Dirk Dockal, Michael Plaimauer, Barbara Rottensteiner, Hanspeter Gritsch, Herbert Federti, Enrica Matte, Alessandro De Franceschi, Lucia Scheiflinger, Friedrich Hoellriegl, Werner eng Research Support, Non-U.S. Gov't England 2023/01/27 J Thromb Haemost. 2023 Feb; 21(2):269-275. doi: 10.1016/j.jtha.2022.10.016. Epub 2022 Dec 22"