Marta-Enguita Juan, Navarro-Oviedo Manuel, Muñoz Roberto, Olier-Arenas Jorge, Zalba Guillermo, Lecumberri Ramon, Mendioroz Maite, Paramo Jose A, Roncal Carmen, Orbe Josune
Laboratory of Atherothrombosis, CIMA-Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
Neurology Service, Complejo Hospitalario de Navarra, IdisNA, Pamplona, Spain.
Front Neurol. 2021 Feb 22;12:599498. doi: 10.3389/fneur.2021.599498. eCollection 2021.
Actual clinical management of ischemic stroke (IS) is based on restoring cerebral blood flow using tissue plasminogen activator (tPA) and/or endovascular treatment (EVT). Mechanical thrombectomy has permitted the analysis of thrombus structural and cellular classic components. Nevertheless, histological assessment of hemostatic parameters such as thrombin-activatable fibrinolysis inhibitor (TAFI) and matrix metalloproteinase 10 (MMP-10) remains unknown, although their presence could determine thrombus stability and its response to thrombolytic treatment, improving patient's outcome. We collected thrombi ( = 45) from large vessel occlusion (LVO) stroke patients ( = 53) and performed a histological analysis of different hemostatic parameters [TAFI, MMP-10, von Willebrand factor (VWF), and fibrin] and cellular components (erythrocytes, leukocytes, macrophages, lymphocytes, and platelets). Additionally, we evaluated the association of these parameters with plasma levels of MMP-10, TAFI and VWF activity and recorded clinical variables. In this study, we report for the first time the presence of MMP-10 and TAFI in all thrombi collected from LVO patients. Both proteins were localized in regions of inflammatory cells, surrounded by erythrocyte and platelet-rich areas, and their content was significantly associated ( = 0.41, < 0.01). Thrombus TAFI was lower in patients who died during the first 3 months after stroke onset [odds ratio (OR) (95%CI); 0.59 (0.36-0.98), = 0.043]. Likewise, we observed that thrombus MMP-10 was inversely correlated with the amount of VWF ( = -0.30, < 0.05). Besides, VWF was associated with the presence of leukocytes ( = 0.37, < 0.05), platelets ( = 0.32, < 0.05), and 3 months mortality [OR (95%CI); 4.5 (1.2-17.1), = 0.029]. Finally, plasma levels of TAFI correlated with circulating and thrombus platelets, while plasma MMP-10 was associated with cardiovascular risk factors and functional dependence at 3 months. The present study suggests that the composition and distribution of thrombus hemostatic components might have clinical impact by influencing the response to pharmacological and mechanical therapies as well as guiding the development of new therapeutic strategies.
缺血性中风（IS）的实际临床管理基于使用组织纤溶酶原激活剂（tPA）和/或血管内治疗（EVT）来恢复脑血流。机械取栓术使得对血栓的结构和细胞经典成分进行分析成为可能。然而，尽管凝血酶激活的纤维蛋白溶解抑制剂（TAFI）和基质金属蛋白酶10（MMP-10）等止血参数的组织学评估仍然未知，但其存在可能决定血栓稳定性及其对溶栓治疗的反应，从而改善患者的预后。我们从大血管闭塞（LVO）中风患者（n = 53）中收集了血栓（n = 45），并对不同的止血参数[TAFI、MMP-10、血管性血友病因子（VWF）和纤维蛋白]以及细胞成分（红细胞、白细胞、巨噬细胞、淋巴细胞和血小板）进行了组织学分析。此外，我们评估了这些参数与MMP-10、TAFI血浆水平和VWF活性的相关性，并记录了临床变量。在本研究中，我们首次报告了从LVO患者收集的所有血栓中均存在MMP-10和TAFI。这两种蛋白均定位于炎症细胞区域，周围是富含红细胞和血小板的区域，且它们的含量显著相关（r = 0.41，P < 0.01）。中风发作后前3个月内死亡的患者血栓TAFI较低[比值比（OR）（95%置信区间）；0.59（0.36 - 0.98），P = 0.043]。同样，我们观察到血栓MMP-10与VWF量呈负相关（r = -0.30，P < 0.05）。此外，VWF与白细胞的存在相关（r = 0.37，P < 0.05）、与血小板相关（r = 0.32，P < 0.05）以及与3个月死亡率相关[OR（95%置信区间）；4.5（1.2 - 17.1），P = 0.029]。最后，TAFI的血浆水平与循环血小板和血栓血小板相关，而血浆MMP-10与心血管危险因素和3个月时的功能依赖相关。本研究表明，血栓止血成分的组成和分布可能通过影响对药物和机械治疗的反应以及指导新治疗策略的开发而产生临床影响。
