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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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The excessive degree of HT and the reversal of anticoagulation with PCC are functionally relevant in a model of milder strokes.A) Mice receiving rt-PA (10 mg/kg) after 1 h MCAO under warfarin treatment (middle, n = 5) show a significantly greater HT volume than control mice (left, n = 6). Reversal of oral anticoagulation with PCC (100 IU/kg) significantly attenuates HT (right, n = 6). *** p<0.001. B) Functional neurological outcome was evaluated on a 14-point neuroscore and statistical significance was assessed with a Kruskal-Wallis test with Dunn's correction, median values are given (5, 11 and 6, ** p<0.01).
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pone-0026087-g004: The excessive degree of HT and the reversal of anticoagulation with PCC are functionally relevant in a model of milder strokes.A) Mice receiving rt-PA (10 mg/kg) after 1 h MCAO under warfarin treatment (middle, n = 5) show a significantly greater HT volume than control mice (left, n = 6). Reversal of oral anticoagulation with PCC (100 IU/kg) significantly attenuates HT (right, n = 6). *** p<0.001. B) Functional neurological outcome was evaluated on a 14-point neuroscore and statistical significance was assessed with a Kruskal-Wallis test with Dunn's correction, median values are given (5, 11 and 6, ** p<0.01).

Mentions: After 1 h MCAO, leading to ischemic lesions of 49.7±25.1 mm3 in our hands (n = 6, data not shown), mice with prior warfarin treatment who received rt-PA at the onset of reperfusion also developed a considerable degree of HT (3.1 µl±0.4, n = 5 vs. 1.0±0.2, in control mice, n = 6, p<0.001) (Fig. 4A). Reversal of warfarin anticoagulation with PCC prior to rt-PA treatment reduced the HT volume considerably (1.7±0.3 µl, n = 6, p<0.001 compared to anticoagulated and rt-PA-treated without restoration of the coagulation system) (Fig. 4A). In this model of milder stroke, the increase of HT in rt-PA-treated mice with prior warfarin anticoagulation translated into a relevant deterioration of the functional neurological outcome (median neuroscore of 11 vs. 5 in control mice, p = 0.01 [Gaussian approximation]). Functional outcome showed a clear, however statistically non-significant tendency to be improved in the mice who were substituted with PCC before they received rt-PA (median neuroscore 6, p>0.05 [Gaussian approximation]) (Fig. 4B). One mouse was excluded from the group with warfarin pretreatment prior to rt-PA due to death secondary to an abdominal bleeding. This mouse was not substituted to the operator. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 5.28 for the comparison of control mice with mice receiving rt-PA after warfarin pretreatment providing a statistical power of 99% and of 2.33 for the comparison of mice receiving rt-PA after warfarin pretreatment with equally-treated mice who had their anticoagulation reversed with PCC prior to rt-PA providing a statistical power of 90%.


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)

The excessive degree of HT and the reversal of anticoagulation with PCC are functionally relevant in a model of milder strokes.A) Mice receiving rt-PA (10 mg/kg) after 1 h MCAO under warfarin treatment (middle, n = 5) show a significantly greater HT volume than control mice (left, n = 6). Reversal of oral anticoagulation with PCC (100 IU/kg) significantly attenuates HT (right, n = 6). *** p<0.001. B) Functional neurological outcome was evaluated on a 14-point neuroscore and statistical significance was assessed with a Kruskal-Wallis test with Dunn's correction, median values are given (5, 11 and 6, ** p<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198453&req=5

pone-0026087-g004: The excessive degree of HT and the reversal of anticoagulation with PCC are functionally relevant in a model of milder strokes.A) Mice receiving rt-PA (10 mg/kg) after 1 h MCAO under warfarin treatment (middle, n = 5) show a significantly greater HT volume than control mice (left, n = 6). Reversal of oral anticoagulation with PCC (100 IU/kg) significantly attenuates HT (right, n = 6). *** p<0.001. B) Functional neurological outcome was evaluated on a 14-point neuroscore and statistical significance was assessed with a Kruskal-Wallis test with Dunn's correction, median values are given (5, 11 and 6, ** p<0.01).
Mentions: After 1 h MCAO, leading to ischemic lesions of 49.7±25.1 mm3 in our hands (n = 6, data not shown), mice with prior warfarin treatment who received rt-PA at the onset of reperfusion also developed a considerable degree of HT (3.1 µl±0.4, n = 5 vs. 1.0±0.2, in control mice, n = 6, p<0.001) (Fig. 4A). Reversal of warfarin anticoagulation with PCC prior to rt-PA treatment reduced the HT volume considerably (1.7±0.3 µl, n = 6, p<0.001 compared to anticoagulated and rt-PA-treated without restoration of the coagulation system) (Fig. 4A). In this model of milder stroke, the increase of HT in rt-PA-treated mice with prior warfarin anticoagulation translated into a relevant deterioration of the functional neurological outcome (median neuroscore of 11 vs. 5 in control mice, p = 0.01 [Gaussian approximation]). Functional outcome showed a clear, however statistically non-significant tendency to be improved in the mice who were substituted with PCC before they received rt-PA (median neuroscore 6, p>0.05 [Gaussian approximation]) (Fig. 4B). One mouse was excluded from the group with warfarin pretreatment prior to rt-PA due to death secondary to an abdominal bleeding. This mouse was not substituted to the operator. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 5.28 for the comparison of control mice with mice receiving rt-PA after warfarin pretreatment providing a statistical power of 99% and of 2.33 for the comparison of mice receiving rt-PA after warfarin pretreatment with equally-treated mice who had their anticoagulation reversed with PCC prior to rt-PA providing a statistical power of 90%.

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