Role of factor XIII in ischemic stroke: a key molecule promoting thrombus stabilization and resistance to lysis

Marta-Enguita J, Navarro-Oviedo M, Machado FJDM et al.  J Thromb Haemost. 2024 Apr;22(4):1080-1093. doi: 10.1016/j.jtha.2023.12.029. Epub 2023 Dec 30. PMID: 38160727

Background: Active coagulation factor XIII (FXIII) catalyzing crosslinking of fibrin and other hemostatic factors plays a key role in clot stability and lysis.
Objectives: To evaluate the effect of FXIII inhibition in a mouse model of ischemic stroke (IS) and the role of activated FXIII (FXIIIa) in clot formation and lysis in patients with IS.
Methods: A ferric chloride IS murine model was performed before and after administration of a FXIIIa inhibitor (FXIIIinh). Thromboelastometry in human and mice blood was used to evaluate thrombus stiffness and lysis with FXIIIinh. FXIIIa-dependent fibrin crosslinking and lysis with fibrinolytic drugs (tissue plasminogen activator and tenecteplase) were studied on fibrin plates and on thrombi and clotted plasma of patients with IS. Finally, circulating and thrombus FXIIIa were measured in 85 patients with IS.
Results: FXIIIinh administration before stroke induction reduced infarct size, α2- antiplasmin (α2AP) crosslinking, and local microthrombosis, improving motor coordination and fibrinolysis without intracranial bleeds (24 hours). Interestingly, FXIII blockade after stroke also reduced brain damage and neurologic deficit. Thromboelastometry in human/mice blood with FXIIIinh showed delayed clot formation, reduced clot firmness, and shortened tissue plasminogen activator lysis time. FXIIIa fibrin crosslinking increased fibrin density and lysis resistance, which increased further after α2AP addition. FXIIIinh enhanced ex vivo lysis in stroke thrombi and fibrin plates. In patients with IS, thrombus FXIII and α2AP were associated with inflammatory and hemostatic components, and plasma FXIIIa correlated with thrombus α2AP and fibrin.

Funding: This work was supported by ISCIII (PI19/00065-PI22/00436”), cofunded by ERDF, “A way to make Europe”; CIBERCV (CB16/11/ 00483); RICORS-ICTUS (RD21/0006/0008); the Spanish Society of Thrombosis and Hemostasis; and Virto S.A. We particularly acknowledge the patients enrolled in this study for their participation, the Biobank of the University of Navarra, and the Aragon Health Sciences Institute in the framework of the Biobank of the Aragon Health System for their collaboration.