Factor XIII Prevents Pulmonary Emboli in Mice by Stabilizing Deep Vein ThrombiFunding This study was partly funded by Canadian Venous Thromboembolism Clinical Trials and Outcomes research (CanVector). J.I. Weitz holds the Canada Research Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation J. Fraser Mustard Chair in Cardiovascular Research. P.Y. Kim holds the Department of Medicine Career Award (McMaster University).
26 September 2018
22 February 2019
20 April 2019 (online)
Background Deep vein thrombosis (DVT) can lead to pulmonary embolism (PE), but the mechanisms responsible for this progression are unknown. Previously, we showed that inhibition of thrombin-mediated activation of factor (F) XIII promotes venous thrombus stability in a murine model.
Aim In this study, we investigate the consequence of attenuating fibrinolysis, using FXIII, α2-antiplasmin (α2-AP) or ε-aminocaproic acid (EACA) supplementation, on clot lysis and venous thrombus stability using the same mouse model.
Methods In vitro plasma clot lysis assay shows that EACA and α2-AP but not FXIII, inhibit fibrinolysis. Ferric chloride induced thrombi in the femoral vein of mice. After thrombus formation, mice received saline, EACA, α2-AP or FXIII, with or without dalteparin or dabigatran. Thrombus sizes and embolization over 2 hours were visualized using intravital videomicroscopy. Lungs were sectioned to quantify emboli presence via histology.
Results The change in thrombus size over time was significantly greater after EACA treatment, but not FXIII or α2-AP supplementation, compared with saline. α2-AP-supplementation did not alter thrombus stability. Thrombi were more stable following EACA treatment and FXIII supplementation as evidenced by less embolic events and PE burden, even when they were anticoagulated with either dalteparin or dabigatran.
Conclusion FXIII supplementation stabilized venous thrombi, even in the presence of anticoagulants, and did not alter thrombus size. Supplemental FXIII may be useful to stabilize DVT and be an alternative adjunctive treatment to minimize PE, even when anticoagulants are used.
S.A.S. performed all experiments, analysed data and results and wrote the manuscript. D.M.G. performed the clot lysis assay. P.Y.K. designed and analysed the clot lysis data, and edited the manuscript. P.L.G. supervised the research, conceived and designed the study. P.L.G. and J.I.W. contributed to the interpretation of data and critically edited the manuscript. All authors have read and approved the article.
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