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

Abstract

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 (rtPAϩTLP). In addition, MCA reactivity was assessed in rtPA-or rtPAϩTLP-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 rtPAϩTLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8Ϯ2.3 petechiae versus 3.0Ϯ1.0 petechiae in rtPA group; PϽ0.001). This increased severity was associated with a significant increase of both infarct volume (182Ϯ10 versus 144Ϯ15 mm 3 in rtPA group; PϽ0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9Ϯ0.5% versus 13Ϯ1% in rtPA group; PϽ0.05). Key Words: hemorrhage Ⅲ ischemia, focal Ⅲ plasmin Ⅲ thrombolysis Ⅲ tissue plasminogen activator T hrombolytic therapy with recombinant tissue plasminogen activator (rtPA) has demonstrated improvement in clinical outcome in acute ischemic stroke. 1,2 However, the threat of intracerebral hemorrhage (ICH) is an important barrier to widespread administration of thrombolytic agents. While many factors, such as elevated blood pressure, diabetes, age, and rtPA administration time, contribute to the occurrence of ICH, the underlying mechanisms remain elusive. [3][4][5] ICH are preferentially located in the infarct area, suggesting a role of ischemia per se. 6,7 In response to ischemic and inflammatory stimuli, vascular modifications may also be involved in ICH pathophysiology. 8 In particular, endothelium-dependent relaxation, a marker of ischemia-induced impairment of cerebral vasculature, 9,10 is worsened in vitro by the application of rtPA. 11 It remains unknown whether rtPA directly induces ICH or if the interaction between rtPA and thrombus, via the resulting thrombolysis products (TLP), is involved. Existence of rtPA-induced ICH in thromboembolic models has been well established, 7,12-15 whereas it remains more uncertain in mechanical models of ischemia. 6,16 The difference between the 2 models suggests that thrombus may contribute to the occurrence of ICH. To test this hypothesis, we compared the effects of rtPA or rtPA-induced TLP in a model of mechanical middle cerebral artery (MCA) occlusion on ICH incidence and severity. We also studied infarct volume and MCA endothelial function to investigate the mechanism of ICH occur...

A Mouse Model of Hemorrhagic Transformation by Delayed Tissue Plasminogen Activator Administration After In Situ Thromboembolic Stroke

“…22 The development of HT after delayed tPA treatment found in our model is consistent with previous studies in other experimental models. 14,[23][24][25][26][27] In contrast with our model in mice, the therapeutic window for tPA in humans might be longer in some cases (4.5 hours). 1 Several reasons may account for this, but very likely it is due to a faster metabolism in mice.…”

The Neurotoxicity of Tissue Plasminogen Activator?

“…Plasmin is also known to activate MMP-9 and MMP-2, thereby forming another important mechanism of tPA induced hemorrhage (Murphy et al, 1992;Mun-Bryce and Rosenberg, 1998). tPA can produce abnormally high levels of plasmin and thrombolysis products (TLPs) that can trigger intracranial hemorrhage and can modulate the severity of hemorrhagic transformation (Gautier et al, 2003). Plasmin contained in TLPs can act on non-fibrinogenic substrates (Tsirka et al, 1997) and compromise cell viability.…”

“…Under basal conditions, tPA mRNA may be continually present but its translation into protein may occur after some significant injury. Various inhibitors of tPA such as type 1 plasminogen activator inhibitor (PAI-1) or neuroserpin can block the protease activity of tPA (Gautier et al, 2003). Recently, Fernandez-Monreal et al (2004) demonstrated that astrocytes can scavenge extracellular tPA by a receptor dependent mechanism.…”

Is Heparin Treatment the Optimal Management for Cerebral Venous Thrombosis?

“…27 In contrast, Gautier could show that rtPA infused 5 hours after middle cerebral artery occlusion leads to intracerebral hemorrhages and increased the size of the infarct. 28 Systemic thrombolysis with rtPA in cerebral sinus and cortical vein occlusion has been performed in 2 experimental studies. Röther et al induced thrombosis of the SSS in rats by ligation and injection of cepahlin suspension.…”