Faculty Collaboration Database

Sustained depletion of FXIII-A by inducing acquired FXIII-B deficiency. Blood 2020 Dec 17;136(25):2946-2954

Date

07/18/2020

Pubmed ID

32678423

Pubmed Central ID

PMC9710420

DOI

10.1182/blood.2020004976

Scopus ID

2-s2.0-85096223268 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

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.

Author List

Strilchuk AW, Meixner SC, Leung J, Safikhan NS, Kulkarni JA, Russell HM, van der Meel R, Sutherland MR, Owens AP, Palumbo JS, Conway EM, Pryzdial ELG, Cullis PR, Kastrup CJ

Author

Christian Kastrup PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Factor XIII
Factor XIII Deficiency
Factor XIIIa
Gene Knockdown Techniques
Hemorrhage
Mice
Mice, Knockout
Nanoparticles
RNA, Small Interfering
Rabbits