Published Online
on November 13, 2003

A more recent version of this article appeared on December 1, 2003

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Submitted on August 5, 2003
Accepted on August 15, 2003

Involvement of Thrombolysis in Recombinant Tissue Plasminogen Activator-Induced Cerebral Hemorrhages and Effect on Infarct Volume and Postischemic Endothelial Function

Sophie Gautier PharmD; Olivier Petrault;; Patrick Gele;; Maud Laprais;; Michelle Bastide PhD; Anne Bauters MD; Dominique Deplanque MD, PhD; Brigitte Jude MD, PhD; Jacques Caron MD; and Régis Bordet MD, PhD^*

From the Laboratoire de Pharmacologie, Faculté de Medecine, Lille, France.

^* To whom correspondence should be addressed. E-mail: bordet{at}univ-lille2.fr.

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 mm³ 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.

Key words: hemorrhage • ischemia, focal • plasmin • thrombolysis • tissue plasminogen activator

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