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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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Reversal of anticoagulation with PCC diminishes the excessive rt-PA-associated risk of hemorrhagic transformation in warfarin-treated mice.A) Anticoagulated mice treated with i.v. rt-PA (10 mg/kg) after 3 h MCAO develop large intracerebral hematomas (left, n = 5). Reversal of oral anticoagulation with i.v. PCC (100 IU/kg) directly before the administration of rt-PA counterbalances the excessive risk of hemorrhagic transformation (right, n = 5). Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.001. 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 5 and 4, p = 0.2738).
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pone-0026087-g003: Reversal of anticoagulation with PCC diminishes the excessive rt-PA-associated risk of hemorrhagic transformation in warfarin-treated mice.A) Anticoagulated mice treated with i.v. rt-PA (10 mg/kg) after 3 h MCAO develop large intracerebral hematomas (left, n = 5). Reversal of oral anticoagulation with i.v. PCC (100 IU/kg) directly before the administration of rt-PA counterbalances the excessive risk of hemorrhagic transformation (right, n = 5). Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.001. 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 5 and 4, p = 0.2738).

Mentions: In effectively anticoagulated mice receiving i.v. rt-PA treatment after 3 h MCAO, the rapid reversal of anticoagulation by means of PCC application directly prior to rt-PA administration significantly reduced the amount of HT as compared to non PCC-treated mice (3.8±0.7 µl, n = 5 in all groups vs. 15.0±3.8 µl, p<0.001) (Fig. 3A). Restoring the coagulation system with PCC reduced the extent of HT to values comparable with those seen in rt-PA treated animals without prior warfarin treatment (2.8±1.0 µl vs. 3.8±0.7 µl, p = 0.12, left column in Fig. 2 and right column in Fig. 3A). In terms of neurological function, mice whose anticoagulation was reversed with PCC showed a non-significant tendency towards a better functional outcome (median 5 vs. 4, p = 0.2738 [Gaussian approximation]) (Fig. 3B). Two mice in the group receiving rt-PA after prior warfarin treatment without anticoagulation reversal with PCC died due to major intracranial hemorrhage including vast subarachnoid hemorrhage. Two mice in the PCC-group had to be excluded due to a failure of i.v. substance application and were substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 7.47 for this comparison 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)

Reversal of anticoagulation with PCC diminishes the excessive rt-PA-associated risk of hemorrhagic transformation in warfarin-treated mice.A) Anticoagulated mice treated with i.v. rt-PA (10 mg/kg) after 3 h MCAO develop large intracerebral hematomas (left, n = 5). Reversal of oral anticoagulation with i.v. PCC (100 IU/kg) directly before the administration of rt-PA counterbalances the excessive risk of hemorrhagic transformation (right, n = 5). Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.001. 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 5 and 4, p = 0.2738).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198453&req=5

pone-0026087-g003: Reversal of anticoagulation with PCC diminishes the excessive rt-PA-associated risk of hemorrhagic transformation in warfarin-treated mice.A) Anticoagulated mice treated with i.v. rt-PA (10 mg/kg) after 3 h MCAO develop large intracerebral hematomas (left, n = 5). Reversal of oral anticoagulation with i.v. PCC (100 IU/kg) directly before the administration of rt-PA counterbalances the excessive risk of hemorrhagic transformation (right, n = 5). Statistical significance was essayed with student's unpaired, two-tailed t-test. ** p<0.001. 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 5 and 4, p = 0.2738).
Mentions: In effectively anticoagulated mice receiving i.v. rt-PA treatment after 3 h MCAO, the rapid reversal of anticoagulation by means of PCC application directly prior to rt-PA administration significantly reduced the amount of HT as compared to non PCC-treated mice (3.8±0.7 µl, n = 5 in all groups vs. 15.0±3.8 µl, p<0.001) (Fig. 3A). Restoring the coagulation system with PCC reduced the extent of HT to values comparable with those seen in rt-PA treated animals without prior warfarin treatment (2.8±1.0 µl vs. 3.8±0.7 µl, p = 0.12, left column in Fig. 2 and right column in Fig. 3A). In terms of neurological function, mice whose anticoagulation was reversed with PCC showed a non-significant tendency towards a better functional outcome (median 5 vs. 4, p = 0.2738 [Gaussian approximation]) (Fig. 3B). Two mice in the group receiving rt-PA after prior warfarin treatment without anticoagulation reversal with PCC died due to major intracranial hemorrhage including vast subarachnoid hemorrhage. Two mice in the PCC-group had to be excluded due to a failure of i.v. substance application and were substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 7.47 for this comparison 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