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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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Hemorrhagic transformation after i.v. thrombolysis with rt-PA is excessively increased in effectively anticoagulated mice.A) Mice without prior warfarin intake subjected to 3 h MCAO were treated with 10 mg/kg human rt-PA directly prior to reperfusion (left, n = 5). In comparison, mice anticoagulated to an INR of approximately 3 at the onset of cerebral ischemia (right, n = 5) showed a vast increase in hematoma volume after t-PA treatment. Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.01. B) Neuroscores were analyzed for statistical significance with a one-tailed Mann Whitney test and the p-value given as a Gaussian approximation (median values 4.5 and 5, p = 0.1970).
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pone-0026087-g002: Hemorrhagic transformation after i.v. thrombolysis with rt-PA is excessively increased in effectively anticoagulated mice.A) Mice without prior warfarin intake subjected to 3 h MCAO were treated with 10 mg/kg human rt-PA directly prior to reperfusion (left, n = 5). In comparison, mice anticoagulated to an INR of approximately 3 at the onset of cerebral ischemia (right, n = 5) showed a vast increase in hematoma volume after t-PA treatment. Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.01. B) Neuroscores were analyzed for statistical significance with a one-tailed Mann Whitney test and the p-value given as a Gaussian approximation (median values 4.5 and 5, p = 0.1970).

Mentions: When comparing the effects of i.v. rt-PA treatment after 3 h MCAO in non-anticoagulated mice and in mice pretreated with oral warfarin to an INR of approximately 3, warfarin pretreatment vastly increased the amount of HT (9.2±3.2 µl vs. 2.8±1 µl, n = 6 in both groups, p<0.05) (Fig. 2A). There was a tendency, however non-significant, towards a more severe neurological deficit in warfarin-treated mice that received rt-PA as compared to mice without prior warfarin intake that received rt-PA (median 5 vs. 4.5, p = 0.1970 [Gaussian approximation]) (Fig. 2B). One mouse receiving rt-PA without prior warfarin treatment had to be excluded due to a failure of i.v. substance application and was substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 4.36 for this comparison providing a statistical power of 99%.


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)

Hemorrhagic transformation after i.v. thrombolysis with rt-PA is excessively increased in effectively anticoagulated mice.A) Mice without prior warfarin intake subjected to 3 h MCAO were treated with 10 mg/kg human rt-PA directly prior to reperfusion (left, n = 5). In comparison, mice anticoagulated to an INR of approximately 3 at the onset of cerebral ischemia (right, n = 5) showed a vast increase in hematoma volume after t-PA treatment. Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.01. B) Neuroscores were analyzed for statistical significance with a one-tailed Mann Whitney test and the p-value given as a Gaussian approximation (median values 4.5 and 5, p = 0.1970).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198453&req=5

pone-0026087-g002: Hemorrhagic transformation after i.v. thrombolysis with rt-PA is excessively increased in effectively anticoagulated mice.A) Mice without prior warfarin intake subjected to 3 h MCAO were treated with 10 mg/kg human rt-PA directly prior to reperfusion (left, n = 5). In comparison, mice anticoagulated to an INR of approximately 3 at the onset of cerebral ischemia (right, n = 5) showed a vast increase in hematoma volume after t-PA treatment. Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.01. B) Neuroscores were analyzed for statistical significance with a one-tailed Mann Whitney test and the p-value given as a Gaussian approximation (median values 4.5 and 5, p = 0.1970).
Mentions: When comparing the effects of i.v. rt-PA treatment after 3 h MCAO in non-anticoagulated mice and in mice pretreated with oral warfarin to an INR of approximately 3, warfarin pretreatment vastly increased the amount of HT (9.2±3.2 µl vs. 2.8±1 µl, n = 6 in both groups, p<0.05) (Fig. 2A). There was a tendency, however non-significant, towards a more severe neurological deficit in warfarin-treated mice that received rt-PA as compared to mice without prior warfarin intake that received rt-PA (median 5 vs. 4.5, p = 0.1970 [Gaussian approximation]) (Fig. 2B). One mouse receiving rt-PA without prior warfarin treatment had to be excluded due to a failure of i.v. substance application and was substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 4.36 for this comparison providing a statistical power of 99%.

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