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

Mitchell, Joanne, Little, Gemma, Bye, Alexander, Gasper, Renato, Unsworth, Amanda ORCID: https://orcid.org/0000-0003-3809-5984, Kriek, Neline, Sage, Tanya, Stainer, Alexander, Sangowawa, Ibidayo, Morrow, Gael, Bastos, Ricardo, Shapiro, Susan, Desborough, Michael, Curry, Nicola, Gibbins, Jonathan, Whyte, Claire, Mutch, Nicola and Jones, Christopher (2023) Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability. Research and Practice in Thrombosis and Haemostasis, 7 (5). p. 100200. ISSN 2475-0379

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Abstract

Background: Factor XIII (FXIII) is an important proenzyme in the haemostatic system. The active plasma-derived enzyme FXIIIa cross-links fibrin fibres within thrombi to increase their mechanical strength and to fibrinolytic inhibitors, specifically 2antiplasmin (2AP) to increase resistance to fibrinolysis. We have previously shown that cellular factor XIII (FXIII-A), which is abundant in the platelet cytoplasm, is externalised onto the activated membrane and cross-links extracellular substrates. The contribution of platelet derived FXIII-A to platelet activation and platelet function has not been extensively studied. Objectives: This study aims to identify the role of platelet factor XIII-A in platelet function. Patients/methods: We have utilised 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. Results: 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. Conclusions: Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation following adhesion and thrombus retraction in addition to its antifibrinolytic roles.