Thrombolytic Toxicity: Blood Brain Barrier Disruption in Human Ischemic Stroke

Abstract

In experimental models of cerebral ischemia, thrombolytic drugs have been demonstrated to have a number of neurovascular toxic effects including blood brain barrier disruption. Early barrier opening caused by focal cerebral ischemia in human stroke can be assessed by the presence of gadolinium enhancement of cerebrospinal fluid, termed 'Hyperintense Acute Injury Marker' (HARM). In a retrospective analysis, the frequency of HARM was studied in 140 patients, 38 receiving intra-arterial thrombolytics, 18 undergoing mechanical embolectomy, 24 receiving intravenous tissue plasminogen activator and 60 patients receiving no acute intervention. HARM was found in 66% of patients undergoing intra-arterial thrombolysis and 50% of patients receiving intravenous tissue plasminogen activator, compared to 28% of patients undergoing mechanical embolectomy and 30% of patients receiving no acute therapy (p = 0.002). Both thrombolytic therapy (p = 0.001) and age (p = 0.001) were independent predictors of HARM. HARM was an independent predictor of hemorrhagic transformation (p = 0.007). This is the first study in humans providing supportive evidence of the neurovascular toxic effects of thrombolytics and suggests that HARM may be used as a biomarker of blood brain barrier disruption in future research of acute stroke therapies.