凝血因子XIII在缺血性卒中中的作用：促进血栓稳定和抵抗溶解的关键分子。

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

作者信息

Marta-Enguita Juan, Navarro-Oviedo Manuel, Machado Florencio J D M, Bermejo Rebeca, Aymerich Nuria, Herrera Maria, Zandio Beatriz, Pagola Jorge, Juega Jesús, Marta-Moreno Javier, Rodriguez Jose-Antonio, Páramo Jose-Antonio, Roncal Carmen, Muñoz Roberto, Orbe Josune

机构信息

Atherothrombosis Laboratory, Cardiovascular Diseases Program, Centro de Investigacion Medica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona Spain; Neurology Department, Hospital Universitario Navarra, Pamplona, Spain; Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Electronic address: https://twitter.com/jmartaen.

出版信息

J Thromb Haemost. 2024 Apr;22(4):1080-1093. doi: 10.1016/j.jtha.2023.12.029. Epub 2023 Dec 30.

DOI:10.1016/j.jtha.2023.12.029

PMID: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.

CONCLUSION

Our results suggest a key role of FXIIIa in thrombus stabilization, α2AP crosslinking, and lysis resistance, with a protective effect of FXIIIinh in an IS experimental model.

摘要

背景

活性凝血因子 XIII（FXIII）催化纤维蛋白和其他止血因子的交联，在血凝块稳定性和溶解中起关键作用。

目的

评估 FXIII 抑制在缺血性中风（IS）小鼠模型中的作用，以及活化的 FXIII（FXIIIa）在 IS 患者血凝块形成和溶解中的作用。

方法

在给予 FXIIIa 抑制剂（FXIIIinh）之前和之后，建立氯化铁 IS 小鼠模型。使用人和小鼠血液中的血栓弹力图来评估 FXIIIinh 对血栓硬度和溶解的影响。在纤维蛋白平板以及 IS 患者的血栓和凝血血浆上，研究 FXIIIa 依赖性纤维蛋白交联以及与纤维蛋白溶解药物（组织型纤溶酶原激活剂和替奈普酶）相关的溶解情况。最后，检测 85 例 IS 患者循环中的和血栓中的 FXIIIa。

结果

在中风诱导前给予 FXIIIinh 可减小梗死面积、减少α2 -抗纤溶酶（α2AP）交联和局部微血栓形成，改善运动协调性和纤维蛋白溶解，且无颅内出血（24 小时）。有趣的是，中风后阻断 FXIII 也可减轻脑损伤和神经功能缺损。用 FXIIIinh 检测人和小鼠血液中的血栓弹力图显示，凝血形成延迟、凝块硬度降低以及组织型纤溶酶原激活剂溶解时间缩短。FXIIIa 纤维蛋白交联增加了纤维蛋白密度和溶解抗性，在添加α2AP 后进一步增加。FXIIIinh 增强了中风血栓和纤维蛋白平板的体外溶解。在 IS 患者中，血栓 FXIII 和α2AP 与炎症和止血成分相关，血浆 FXIIIa 与血栓α2AP 和纤维蛋白相关。