Involvement of thrombolysis in recombinant tissue plasminogen activator-induced cerebral hemorrhages and effect on infarct volume and postischemic endothelial function

Background and Purpose-In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. Methods-Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA ( 10 mg/kg) associated with TLP (rtPA + TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA + TLP-treated SHR versus control Wistar-Kyoto rats or SHR. Results-No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA + TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8+/-2.3 petechiae versus 3.0+/-1.0 petechiae in rtPA group; P<0.001). This increased severity was associated with a significant increase of both infarct volume (182+/-10 versus 144+/-15 mm(3) in rtPA group; P<0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9+/-0.5% versus 13+/-1% in rtPA group; P<0.05). Conclusions-Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.