Journal
BLOOD
Volume 136, Issue 25, Pages 2946-2954Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020004976
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Funding
- Canadian Institutes of Health Research (CIHR) [FDN-148370, MSH-130166]
- Natural Sciences and Engineering Research Council (NSERC) [RGPIN 2018-04918]
- Michael Smith Foundation for Health Research [16498]
- Canadian Foundation for Innovation [31928]
- Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
- Heart and Stroke Foundation of Canada (HSFC) [G-19-0026524]
- Canada Research Chairs
- CIHR
- NSERC
- HSFC
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The activated form of coagulation factor XIII (FXIII-A(2)B(2)), 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 alpha 2-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-A(2)B(2) activity.
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