Sustained depletion of FXIII-A by inducing acquired FXIII-B deficiency.

Autor:	Strilchuk AW; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Meixner SC; Centre for Blood Research, and., Leung J; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Safikhan NS; Centre for Blood Research, and., Kulkarni JA; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Russell HM; Pathobiology and Molecular Medicine, Department of Internal Medicine, The University of Cincinnati College of Medicine, Cincinnati, OH; and., van der Meel R; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Sutherland MR; Centre for Blood Research, and., Owens AP; Pathobiology and Molecular Medicine, Department of Internal Medicine, The University of Cincinnati College of Medicine, Cincinnati, OH; and., Palumbo JS; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Conway EM; Centre for Blood Research, and., Pryzdial ELG; Centre for Blood Research, and., Cullis PR; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Kastrup CJ; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Dec 17; Vol. 136 (25), pp. 2946-2954.
DOI:	10.1182/blood.2020004976
Abstrakt:	The activated form of coagulation factor XIII (FXIII-A2B2), FXIII-A*, is a hemostatic enzyme essential for inhibiting fibrinolysis by irreversibly crosslinking fibrin and antifibrinolytic proteins. Despite its importance, there are no modulatory therapeutics. Guided by the observation that humans deficient in FXIII-B have reduced FXIII-A without severe bleeding, we hypothesized that a suitable small interfering RNA (siRNA) targeting hepatic FXIII-B could safely decrease FXIII-A. Here we show that knockdown of FXIII-B with siRNA in mice and rabbits using lipid nanoparticles resulted in a sustained and controlled decrease in FXIII-A. The concentration of FXIII-A in plasma was reduced by 90% for weeks after a single injection and for more than 5 months with repeated injections, whereas the concentration of FXIII-A in platelets was unchanged. Ex vivo, crosslinking of α2-antiplasmin and fibrin was impaired and fibrinolysis was enhanced. In vivo, reperfusion of carotid artery thrombotic occlusion was also enhanced. Re-bleeding events were increased after challenge, but blood loss was not significantly increased. This approach, which mimics congenital FXIII-B deficiency, provides a potential pharmacologic and experimental tool to modulate FXIII-A2B2 activity. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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