Cerebral Hemorrhage Produced by Thrombolytic and Anti-Thrombotic Agents: A Review

Although tissue-type plasminogen activator (t-PA) is believed to be beneficial in the treatment of acute strokes, t-PA treatment increases the risk of symptomatic cerebral hemorrhage. Therefore, the possibility of a fatal complication of cerebral hemorrhage may limit the potential benefits of anti-thrombotic and thrombolytic agents. The potential mechanisms of hemorrhage may be activated by an increase of plasmin activity that produces systemic hemostatic defects. Furthermore, plasmin activates matrix metalloproteinases (MMPs), which degrade extracellular matrix components including laminin and fibronectin. The impairment of vascular integrity and the production of hemorrhage then follow. It has been reported that MMP activity increased in hemorrhagic transformation after cerebral ischemia / reperfusion injury in primates, and that the activated forms of MMPs may play an essential role in opening the blood-brain barrier and in cerebral hemorrhage. Recently, two spin trap agents and a metalloproteinase inhibitor have been reported to reduce cerebral hemorrhage following thrombotic stroke. Although it is unclear by what mechanism(s) free radicals may increase MMP expression, these findings suggest that free radicals and MMPs may play essential roles in cerebral hemorrhage from the treatments with thrombolytic and anti-thrombotic agents in acute strokes. We demonstrated that a free radical scavenger inhibited cerebral hemorrhage produced by heparin, and that the combination of heparin and such a free radical scavenger reduced infarct size and improved neurological symptoms. Our observations point to combination therapy with thrombolytic or anti-thrombotic agents and a free radical scavenger having implications for treatment of acute stroke in human.