脑卒中溶栓后出血转化的发生机制及治疗药物研究进展

Advances in the study of mechanism of thrombolysis-induced hemorrhagic transformation and therapeutic drugs

出血转化(hemorrhagictransformation,HT)是急性脑卒中及其溶栓治疗的主要并发症,是组织纤溶酶原激活剂(tissue plasminogen activator, t-PA)溶栓后致死和致残的主要原因。使用t-PA溶栓可以使HT的发生率增加10倍,死亡率达60%。较窄的治疗时间窗及较高的HT发生率限制了t-PA的临床应用,只有约3.4%~5.2%的急性脑卒中患者能够接受t-PA治疗。由于HT发生机制和治疗靶点不明,临床尚无有效防治药物。HT发生的主要机制是血脑屏障的完整性丧失和神经血管稳态的破坏,涉及多种分子信号通路。在动物及临床研究中已经发现一些药物与t-PA联用能够降低HT的发生,增加溶栓治疗的安全性。本文就近年来溶栓引起HT的发生机制、靶点和治疗药物进行综述,为HT的基础研究及药物研发提供参考。

Hemorrhagic transformation （HT） is a common complication of ischemic stroke, especially after thrombolytic therapy, which is associated with increased morbidity and mortality. Thrombolysis with tissue plasminogen activator （t-PA） increases the rate of HT by as much as 10-fold, and the mortality by about 60%. The patients who are eligible for t-PA treatment are still between 3.4% and 5.2% of all patients with acute ischemic stroke because of the narrow therapeutic time window. Due to the unknown mechanism and therapeutic target of HT, there are no effective drugs to decrease the incidence of HT. The main mechanism of HT is disruption of the blood-brain barrier （BBB） integrity and neurovascular homeostasis, involving a variety of molecular signaling pathways. In animal and clinical studies, combining therapeutic agents with t-PA, which may help to minimize BBB perturbations, reduces the incidence of HT and increases the safety of thrombolytic therapy. This article is prepared to review the mechanisms, targets and therapeutic drugs of t-PA induced HT in recent years to provide a reference to the basic research and drug development of HT.