Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA. Electronic address: https://twitter.com/SajalAkkipeddi.
Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
J Thromb Haemost. 2024 May;22(5):1410-1420. doi: 10.1016/j.jtha.2024.01.013. Epub 2024 Jan 29.
Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps all contribute to acute ischemic stroke thrombus integrity.
In this study, we explored how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics.
Twenty-six retrieved stroke thromboemboli were portioned into 4 segments, with each subjected to 1 hour of in vitro lysis at 37 °C in 1 of 4 solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS-13, tPA + DNA-cleaving deoxyribonuclease (DNase) I, and all 3 enzymes. Lysis, characterized by the percent change in prelysis and postlysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis.
Solutions containing DNase resulted in approximately 3-fold greater thrombolysis than that with the standard-of-care tPA solution (post hoc Tukey, P < .01 for all). DNA content was directly related to lysis in solutions containing DNase (Spearman's ρ > 0.39 and P < .05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman's ρ < -0.40 and P < .05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated).
This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke.
纤维蛋白、血管性血友病因子和中性粒细胞细胞外陷阱中的细胞外 DNA 均有助于急性缺血性脑卒中血栓的完整性。
本研究旨在探讨从急性缺血性脑卒中患者体内取出的血栓的蛋白质组组成与不同溶栓药物的溶栓敏感性之间的关系。
将 26 个取自急性缺血性脑卒中患者的血栓样本分成 4 段，每段在 37°C 的 4 种溶液中孵育 1 小时，这 4 种溶液分别为组织型纤溶酶原激活物（tPA）、tPA+血管性血友病因子裂解 ADAMTS-13、tPA+DNA 裂解脱氧核糖核酸酶（DNase）I 和这 3 种酶的混合物。通过孵育前后的重量变化来衡量溶栓效果，并对不同溶液之间的溶栓效果进行比较，同时将其与每种溶栓溶液所对应的血栓样本的质谱分析结果中的蛋白质丰度进行相关分析。
与标准 tPA 溶液相比，含有 DNase 的溶液的溶栓效果大约提高了 3 倍（事后 Tukey 检验，所有溶液均 P<.01）。在含有 DNase 的溶液中，DNA 含量与溶栓效果直接相关（Spearman's ρ > 0.39，所有有统计学意义的组蛋白 P<.05），而在不含 DNase 的溶液中，DNA 含量与溶栓效果呈负相关（Spearman's ρ < -0.40，所有有统计学意义的组蛋白 P<.05）。功能分析表明，tPA（血小板介导）或 DNase（固有免疫系统介导）与溶栓敏感性相关的途径不同。
本研究证明了 DNase 和 tPA 在溶栓治疗中的协同作用，并指出 DNase 可能是治疗急性缺血性脑卒中时现有溶栓药物的一种潜在辅助药物。
