Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability.

Mitchell, Joanne L.; Little, Gemma; Bye, Alexander P.; Gaspar, Renato S.; Unsworth, Amanda J.; Kriek, Neline; Sage, Tanya; Stainer, Alexander; Sangowawa, Ibidayo; Morrow, Gael B.; Bastos, Ricardo N.; Shapiro, Susan; Desborough, Michael J.R.; Curry, Nicola; Gibbins, Jonathan M.; Whyte, Claire S.; Mutch, Nicola J.; Jones, Christopher I.

Abstract

Factor XIII (FXIII) is an important proenzyme in the hemostatic system. The plasma-derived enzyme activated FXIII cross-links fibrin fibers within thrombi to increase their mechanical strength and cross-links fibrin to fibrinolytic inhibitors, specifically α2-antiplasmin, to increase resistance to fibrinolysis. We have previously shown that cellular FXIII (factor XIII-A [FXIII-A]), which is abundant in the platelet cytoplasm, is externalized onto the activated membrane and cross-links extracellular substrates. The contribution of cellular FXIII-A to platelet activation and platelet function has not been extensively studied. This study aims to identify the role of platelet FXIII-A in platelet function. We used normal healthy platelets with a cell permeable FXIII inhibitor and platelets from FXIII-deficient patients as a FXIII-free platelet model in a range of platelet function and clotting tests. Our data demonstrate that platelet FXIII-A enhances fibrinogen binding to the platelet surface upon agonist stimulation and improves the binding of platelets to fibrinogen and aggregation under flow in a whole-blood thrombus formation assay. In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P-selectin exposure and fibrinogen binding. We show that FXIII-A is involved in platelet spreading where a lack of FXIII-A reduces the ability of platelets to fully spread on fibrinogen and collagen. Our data demonstrate that platelet FXIII-A is important for clot retraction where clots formed in its absence retracted to a lesser extent. Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation and thrombus retraction in addition to its antifibrinolytic roles.

Citation

MITCHELL, J.L., LITTLE, G., BYE, A.P. et al. 2023. Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability. Research and practice in thrombosis and haemostasis [online], 7(5), article 100200. Available from: https://doi.org/10.1016/j.rpth.2023.100200

• Journal Article Type: Article
• Acceptance Date: May 23, 2023
• Online Publication Date: Jun 7, 2023
• Publication Date: Jul 31, 2023
• Deposit Date: Aug 7, 2023
• Publicly Available Date: Aug 14, 2023
• Journal: Research and practice in thrombosis and haemostasis
• Electronic ISSN: 2475-0379
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 5
• Article Number: 100200
• DOI: https://doi.org/10.1016/j.rpth.2023.100200
• Keywords: Clot retraction; Factor XIII; Fibrinogen; Fibrinolysis; Platelet activation; Platelet
• Public URL: https://rgu-repository.worktribe.com/output/2034976