Publicaciones

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

https://pubmed.ncbi.nlm.nih.gov/38160727/

Abstract:
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.

Development of Pharmacological Strategies with Therapeutic Potential in Ischemic Stroke

Escobar-Peso A, Martínez-Alonso E, Masjuan J, Alcázar A. Antioxidants (Basel). 2023 Dec 12;12(12):2102. doi: 10.3390/antiox12122102. PMID: 38136221

https://pubmed.ncbi.nlm.nih.gov/38136221/

Abstract: Acute ischemic stroke constitutes a health challenge with great social impact due to its high incidence, with the social dependency that it generates being an important source of inequality. The lack of treatments serving as effective neuroprotective therapies beyond thrombolysis and thrombectomy is presented as a need. With this goal in mind, our research group’s collaborative studies into cerebral ischemia and subsequent reperfusion concluded that there is a need to develop compoundswith antioxidant and radical  scavenger features. In this review, we summarize the path taken toward the identification of lead compounds as potential candidates for the treatment of acute ischemic stroke. Evaluations of the antioxidant capacity, neuroprotection of primary neuronal cultures and in vivo experimental models of cerebral ischemia, including neurological deficit score assessments, are conducted to characterize the biological efficacy of the various neuroprotective compounds developed. Moreover, the initial results in preclinical development, including dose–response studies, the therapeutic window, the long-term neuroprotective effect and in vivo antioxidant evaluation, are reported. The results prompt these c mpounds for clinical trials and are encouraging regarding new drug developments aimed at a successful therapy for ischemic stroke.

Funding: This work was funded by Instituto de Salud Carlos III through the projects PI22/01381 and RICORS RD21/0006/0019 and co-funded by the European Union. A.E.-P. and E.M.-A. thank the Instituto de Salud Carlos III for the contracts IFI18/00011 and RD21/0006/0019, respectively, co-funded by the European Union.