Evolution of intracerebral hemorrhage after intravenous tPA: reversal of harmful effects with mast cell stabilization

Abstract

Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean±s.d. 83.5±14.3 versus 66.7±14.7 μL; P=0.256) or hemispheric expansion (14.5±5.0 versus 11.5±5.0%; P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4±1.7 versus 14.5±5.0%; P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings.

Figure 1

Representative T2*-weighted magnetic resonance images from each group during follow-up.

Figure 2

Development of hematoma volume during follow-up measured from T2*-images. All groups showed equal hematoma volumes at the beginning of the experiment. The most prominent hematoma volumes were present at 24 hours. No significant differences were seen during follow-up (Kruskal–Wallis analysis of variance between-group differences P=0.523 at 55 minutes, P=0.189 at 2 hours, P=0.199 at 24 hours, P=0.247 at 48 hours, and P=0.256 at 72 hours). Data as mean±s.d. tPA, tissue plasminogen activator.

Figure 3

Evolution of hemispheric expansion after intracerebral hemorrahge (ICH). No differences were seen 55 minutes after ICH induction. Differences between saline and tissue plasminogen activator (tPA) groups were not statistically different at any time point, whereas cromoglycate groups showed significant reduction in hemispheric expansion throughout follow-up. Kruskal–Wallis analysis of variance between-group differences: P=0.474 at 55 minutes, P=0.016 at 2 hours, P=0.005 at 24 hours, P=0.029 at 48 hours, and P=0.041 at 72 hours; post hoc comparisons: *=P<0.05, **=P<0.01; significant differences were also seen between saline and tPA+low-dose cromoglycate groups at 24 hours, and saline and tPA+high-dose cromoglycate groups at 72 hours (P<0.05, not shown in figure). Data as mean±s.d.

Figure 4

Neurologic scores during follow-up. Gray bars represent median values. Kruskal–Wallis analysis of variance between-group differences: P=0.053 at 24 hours, P=0.006 at 48 hours, and P=0.002 at 72 hours; post hoc comparisons: *=P<0.05, ***=P<0.001.

Figure 5

Kaplan–Meier survival curves for each treatment group. The lowest survival rate was present in the tissue plasminogen activator (tPA) only group, whereas it significantly improved by applying cromoglycate, most notably in the high-dose group, where all except one animal survived the whole follow-up period.