Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.
Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.
复制标题
tPA 溶栓后利伐沙班减少脑出血与 PAR-1 和 PAR-2 的下调相关。
DOI：
10.1002/jnr.24013
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Abe K.
中科院分区：
文献类型：
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作者：
Morihara R;Yamashita T;Kono S;Shang J;Nakano Y;Sato K;Hishikawa N;Ohta Y;Heitmeier S;Perzborn E;Abe K.
本研究旨在评估与蛋白酶激活受体-1、-2、-3和-4（PAR-1、-2、-3和-4）的激活特征相关的缺血后，与华法林预处理的雄性Wistar大鼠脑相比，利伐沙班治疗后组织型纤溶酶原激活剂（tPA）的脑出血（ICH）风险。用华法林（0.2 mg/kg/天）、低剂量利伐沙班（60 mg/kg/天）、高剂量利伐沙班（120 mg/kg/天）或溶剂预处理14天后，诱导短暂大脑中动脉闭塞90分钟，然后用tPA（10 mg/kg/10 ml）再灌注。检查CT容积、出血量、免疫球蛋白G渗漏和血液参数。再灌注后24小时，在脑切片中进行PAR的免疫组织化学。与利伐沙班治疗组相比，华法林预治疗组的ICH体积增加。PAR-1、PAR-2、PAR-3和PAR-4在正常脑组织中广泛表达，在缺血性脑组织中表达增加，尤其是在缺血性脑损伤中。Warrantine预处理增强了缺血性损伤中PAR-1和PAR-2的表达，而利伐沙班预处理则没有。本研究显示，与华法林预处理的大鼠相比，利伐沙班预处理的大鼠在缺血性脑中给予tPA后脑出血的风险较低。这表明，与华法林预处理相比，利伐沙班对PAR-1和PAR-2的相对下调可能部分参与了临床试验中接受利伐沙班患者出血并发症减少的机制。© 2016 Wiley Periodicals，Inc.
This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue‐type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin‐pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease‐activated receptor‐1, ‐2, ‐3, and ‐4 (PAR‐1, ‐2, ‐3, and ‐4). After pretreatment with warfarin (0.2 mg/kg/day), low‐dose rivaroxaban (60 mg/kg/day), high‐dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty‐four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin‐pretreated group compared with the rivaroxaban‐treated group. PAR‐1, ‐2, ‐3, and ‐4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri‐ischemic lesion. Warfarin pretreatment enhanced the expression of PAR‐1 and PAR‐2 in the peri‐ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban‐pretreated compared with warfarin‐pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR‐1 and PAR‐2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.