Keric Naureen, Döbel Melanie, Krenzlin Harald, Kurz Elena, Tanyildizi Yasemin, Heimann Axel, König Jochem, Kempski Oliver, Ringel Florian, Masomi-Bornwasser Julia
Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
J Stroke Cerebrovasc Dis. 2020 Sep;29(9):105073. doi: 10.1016/j.jstrokecerebrovasdis.2020.105073. Epub 2020 Jun 29.
Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral and intraventricular haemorrhage (ICH and IVH). However, the MISTIE III and CLEAR III trial failed to show significant improvement of favourable outcomes. Besides experimental and clinical trials revealed neurotoxic effects of rtPA. The demand for optimization of fibrinolytic therapy persists. Herein, we used our recently devised clot model of ICH to systematically analyse fibrinolytic properties of rtPA, tenecteplase and urokinase.
In vitro clots of human blood (size: 25 ml and 50 ml; age: 1.5 tenecteplase, 24 tenecteplase and 48 tenecteplase) were produced and equipped with a catheter into the clot core for drug delivery and drainage. Various doses of tenecteplase and urokinase with different treatment periods were examined (overall 117 clots), assessing the optimal dose and treatment time of these fibrinolytics. Clots were weighed before and at the end of treatment. These results were compared with clots treated with 1 mg rtPA or with 0.9% sodium chloride solution.
The optimal treatment scheme of tenecteplase was found to be 100 IU with an incubation time of 30 min, for urokinase it was 50 000 IU with an incubation time of 20 min. The relative clot end weight of tenecteplase and urokinase (31.3±11.9%, 34.8 ±7.7%) was comparable to rtPA (36.7±10.7%). Larger clots were more effectively treated with tenecteplase compared to the control group (P=0.0013). urokinase and tenecteplase had similar lysis rates in aged clots and 90 min clots. One and two repetitive treatments with tenecteplase were as effective as two and three cycles of urokinase.
In our in vitro clot model we could determine optimal treatment regimens of tenecteplase (100 IU, 30 min) and urokinase (50 000 IU, 20 min). Urokinase and tenecteplase were comparable in their fibrinolytic potential compared to 1mg rtPA in small clots and showed an effective lysis in aged clots. tenecteplase was more effective in larger clots.
使用重组组织型纤溶酶原激活剂（rtPA）进行血肿溶解已成为自发性脑内和脑室内出血（ICH和IVH）的一种替代疗法。然而，MISTIE III和CLEAR III试验未能显示出良好结局有显著改善。此外，实验和临床试验揭示了rtPA的神经毒性作用。对优化纤溶治疗的需求依然存在。在此，我们使用我们最近设计的ICH血凝块模型系统地分析rtPA、替奈普酶和尿激酶的纤溶特性。
制备人血的体外血凝块（大小：25 ml和50 ml；时间：1.5小时、24小时和48小时），并在血凝块核心置入一根导管用于药物输送和引流。检测不同剂量的替奈普酶和尿激酶以及不同治疗时长（共117个血凝块），评估这些纤溶剂的最佳剂量和治疗时间。在治疗前和治疗结束时对血凝块进行称重。将这些结果与用1 mg rtPA或0.9%氯化钠溶液治疗的血凝块进行比较。
发现替奈普酶的最佳治疗方案是100 IU，孵育时间为30分钟，尿激酶的最佳治疗方案是50000 IU，孵育时间为20分钟。替奈普酶和尿激酶的血凝块最终相对重量（31.3±11.9%，34.8±7.7%）与rtPA（36.7±10.7%）相当。与对照组相比，替奈普酶对较大血凝块的治疗更有效（P = 0.0013）。尿激酶和替奈普酶在老化血凝块和90分钟血凝块中的溶解率相似。替奈普酶进行一次和两次重复治疗与尿激酶进行两次和三次循环治疗效果相同。
在我们的体外血凝块模型中，我们可以确定替奈普酶（100 IU，30分钟）和尿激酶（50000 IU，20分钟）的最佳治疗方案。与1 mg rtPA相比，尿激酶和替奈普酶在小血凝块中的纤溶潜力相当，并且在老化血凝块中显示出有效的溶解效果。替奈普酶对较大血凝块更有效。
