Endogenous tissue plasminogen activator increases hemorrhagic transformation induced by heparin after ischemia reperfusion in rat brains

Objective: Tissue plasminogen activator (tPA) as a main thrombolytic drug for acute ischemic stroke remains complicated by risk of hemorrhagic transformation. However, whether endogenous tPA is also involved in hemorrhagic transformation is yet unclear. Methods: We randomly assigned male Sprague-Dawley rats into three groups: the heparin group, the control group and the sham operated group. The ischemic rat models were induced by middle cerebral artery occlusion through intraluminal thread technique for 2 hours, followed by 24 hours of reperfusion. Heparin or saline was intermittent peritoneally injected after reperfusion. The extent of cerebral hemorrhage, the infarct volume, as well as the content and activity of endogenous tPA were evaluated. The matrix metalloproteinase 9 (MMP-9) expression and activity were also measured. Results: All rats receiving heparin after reperfusion were subjected to hemorrhagic transformation. Hemorrhage volume in the heparin group was remarkably present. There was significant difference between the two groups (p<0.01). In the heparin group, the expressions of endogenous tPA and MMP-9 obviously increased, while their content and activity had significant differences compared with that of the control group (p<0.01). Conclusion: Endogenous tPA, through enhancement of MMP-9 expression and proteolytic activation, plays an important role in the pathogenesis of hemorrhagic transformation after cerebral reperfusion induced by heparin.