Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PLoS One. 2013;8(2):e54203. doi: 10.1371/journal.pone.0054203. Epub 2013 Feb 8.
Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy.
组织型纤溶酶原激活物（tPA）是唯一获得美国食品药品监督管理局批准用于再灌注缺血性中风的治疗药物。但是，由于担心无意中在伴有颅内出血（ICH）的患者中使用 tPA，其广泛应用仍然受到限制。然而，令人惊讶的是，tPA 会加重 ICH 的假设从未经过生物学测试。在这里，我们在两种 ICH 模型中评估了 tPA 的作用。在胶原酶诱导的 ICH 小鼠模型中，24 小时后生理盐水对照组和 tPA 治疗组的出血体积和神经功能缺损相似，而肝素治疗组的血肿体积则增加了 3 倍。在激光诱导血管破裂模型中，tPA 也没有加重出血体积，而肝素则加重了出血体积。tPA 在脑缺血期间通过放大基质金属蛋白酶而加重神经血管损伤。相比之下，tPA 在我们的 ICH 小鼠模型中并未上调基质金属蛋白酶。总之，我们的实验数据不支持 tPA 在急性 ICH 中有有害作用的假设。然而，由于潜在的物种差异以及模型无法完全捕捉到人类 ICH 的动态，在考虑这些发现对人类治疗的影响时应谨慎。
