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Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC.

Pfeilschifter W, Spitzer D, Pfeilschifter J, Steinmetz H, Foerch C - PLoS ONE (2011)

Bottom Line: To achieve effective anticoagulation, warfarin was administered orally.The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. w.pfeilschifter@med.uni-frankfurt.de

ABSTRACT

Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.

Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.

Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).

Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

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Comparison of hemorrhagic transformation 24 h after MCAO in mice with different antithrombotic pretreatment.A) Comparison of HT volumes in mice who received i.v. thrombolysis with 10 mg/kg human recombinant t-PA directly prior to reperfusion (middle, n = 5) and mice who were effectively anticoagulated to an INR of approximately 3 at the onset of 3 h MCAO (right, n = 4 after exclusion of outlier, see Fig. S1) with mice who underwent 3 h MCAO without any treatment (left, n = 5). Hematoma volume was determined by a hemoglobin assay. Data are depicted as box and whiskers plots showing the 25 to 75 interquartile range and the extreme values. Statistical significance was analyzed with ANOVA and bonferroni correction for multiple testing. *** p<0.001. B) Neuroscores were assessed for statistical significance with a Kruskal-Wallis test and Dunn's correction. Differences between groups were not significant (median values 4, 4 and 5).
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pone-0026087-g001: Comparison of hemorrhagic transformation 24 h after MCAO in mice with different antithrombotic pretreatment.A) Comparison of HT volumes in mice who received i.v. thrombolysis with 10 mg/kg human recombinant t-PA directly prior to reperfusion (middle, n = 5) and mice who were effectively anticoagulated to an INR of approximately 3 at the onset of 3 h MCAO (right, n = 4 after exclusion of outlier, see Fig. S1) with mice who underwent 3 h MCAO without any treatment (left, n = 5). Hematoma volume was determined by a hemoglobin assay. Data are depicted as box and whiskers plots showing the 25 to 75 interquartile range and the extreme values. Statistical significance was analyzed with ANOVA and bonferroni correction for multiple testing. *** p<0.001. B) Neuroscores were assessed for statistical significance with a Kruskal-Wallis test and Dunn's correction. Differences between groups were not significant (median values 4, 4 and 5).

Mentions: After 3 h MCAO, leading to ischemic lesions of 111.6±35.4 mm3 in our hands (n = 6, data not shown), the extent of HT in untreated animals was found to be very low (0.8±0.1 µl, n = 5) (Fig. 1A). In mice without prior warfarin treatment mice receiving i.v. rt-PA (10 mg/ml) immediately prior to reperfusion, the degree of HT increased five-fold (4.0±0.5 µl, n = 5, p<0.001 compared to vehicle-treated mice) (Fig. 1A). Mice pretreated with warfarin to an INR of approximately 3 prior to MCAO also showed a significantly higher degree of HT compared to control mice (4.9±0.5 µl, n = 4, p<0.001 compared to anticoagulation-naïve mice) (Fig. 1A). After 3 h MCAO, all mice showed a severe neurological deficit, and no differences between groups were observed (Fig. 1B). One mouse in the control group and and one mouse in the warfarin group had to be excluded due to failure of i.v. substance application (vehicle in both cases). Corresponding mice were substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 5.77 for the comparison of control mice with mice receiving rt-PA and of 7.25 for the comparison of control mice with warfarin-treated mice both providing a statistical power of 100%.


Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC.

Pfeilschifter W, Spitzer D, Pfeilschifter J, Steinmetz H, Foerch C - PLoS ONE (2011)

Comparison of hemorrhagic transformation 24 h after MCAO in mice with different antithrombotic pretreatment.A) Comparison of HT volumes in mice who received i.v. thrombolysis with 10 mg/kg human recombinant t-PA directly prior to reperfusion (middle, n = 5) and mice who were effectively anticoagulated to an INR of approximately 3 at the onset of 3 h MCAO (right, n = 4 after exclusion of outlier, see Fig. S1) with mice who underwent 3 h MCAO without any treatment (left, n = 5). Hematoma volume was determined by a hemoglobin assay. Data are depicted as box and whiskers plots showing the 25 to 75 interquartile range and the extreme values. Statistical significance was analyzed with ANOVA and bonferroni correction for multiple testing. *** p<0.001. B) Neuroscores were assessed for statistical significance with a Kruskal-Wallis test and Dunn's correction. Differences between groups were not significant (median values 4, 4 and 5).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198453&req=5

pone-0026087-g001: Comparison of hemorrhagic transformation 24 h after MCAO in mice with different antithrombotic pretreatment.A) Comparison of HT volumes in mice who received i.v. thrombolysis with 10 mg/kg human recombinant t-PA directly prior to reperfusion (middle, n = 5) and mice who were effectively anticoagulated to an INR of approximately 3 at the onset of 3 h MCAO (right, n = 4 after exclusion of outlier, see Fig. S1) with mice who underwent 3 h MCAO without any treatment (left, n = 5). Hematoma volume was determined by a hemoglobin assay. Data are depicted as box and whiskers plots showing the 25 to 75 interquartile range and the extreme values. Statistical significance was analyzed with ANOVA and bonferroni correction for multiple testing. *** p<0.001. B) Neuroscores were assessed for statistical significance with a Kruskal-Wallis test and Dunn's correction. Differences between groups were not significant (median values 4, 4 and 5).
Mentions: After 3 h MCAO, leading to ischemic lesions of 111.6±35.4 mm3 in our hands (n = 6, data not shown), the extent of HT in untreated animals was found to be very low (0.8±0.1 µl, n = 5) (Fig. 1A). In mice without prior warfarin treatment mice receiving i.v. rt-PA (10 mg/ml) immediately prior to reperfusion, the degree of HT increased five-fold (4.0±0.5 µl, n = 5, p<0.001 compared to vehicle-treated mice) (Fig. 1A). Mice pretreated with warfarin to an INR of approximately 3 prior to MCAO also showed a significantly higher degree of HT compared to control mice (4.9±0.5 µl, n = 4, p<0.001 compared to anticoagulation-naïve mice) (Fig. 1A). After 3 h MCAO, all mice showed a severe neurological deficit, and no differences between groups were observed (Fig. 1B). One mouse in the control group and and one mouse in the warfarin group had to be excluded due to failure of i.v. substance application (vehicle in both cases). Corresponding mice were substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 5.77 for the comparison of control mice with mice receiving rt-PA and of 7.25 for the comparison of control mice with warfarin-treated mice both providing a statistical power of 100%.

Bottom Line: To achieve effective anticoagulation, warfarin was administered orally.The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. w.pfeilschifter@med.uni-frankfurt.de

ABSTRACT

Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.

Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.

Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).

Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

Show MeSH
Related in: MedlinePlus