Abstract
BackgroundOral 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.Methods62 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.ResultsIn 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).ConclusionIn 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.
Highlights
Intravenous thrombolysis with recombinant tissue plasminogen activator reduces death and disability when administered within the first 4.5 h after symptom onset in patients with ischemic stroke, the pooled data of the large thrombolysis in stroke trials (ECASS, ATLANTIS, NINDS, and EPITHET) revealed that the risk of symptomatic intracerebral hemorrhage is considerably elevated in rt-PA patients (5.2%) as compared to controls (1.0%) [1]
We evaluated whether the rapid reversal of anticoagulation using prothrombin complex concentrates (PCC) just before rt-PA administration reduces the risk of excess hemorrhagic transformation (HT) caused by effective warfarin treatment
Since we have previously shown that the Oral anticoagulant therapy (OAT)-associated increase in HT after cerebral ischemia largely depends on reperfusion [7], we assume that the compromised coagulation system leads to a prolongation and increase of microbleeds which occur naturally at the blood-brain barrier in the course of a large hemispheric infarction
Summary
Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) reduces death and disability when administered within the first 4.5 h after symptom onset in patients with ischemic stroke, the pooled data of the large thrombolysis in stroke trials (ECASS, ATLANTIS, NINDS, and EPITHET) revealed that the risk of symptomatic intracerebral hemorrhage is considerably elevated in rt-PA patients (5.2%) as compared to controls (1.0%) [1]. A recent, vividly debated report on 107 warfarin-treated stroke patients who were eligible for rt-PA treatment due to subtherapeutic INR values of ,1.7 showed an increased rate of symptomatic intracerebral hemorrhage in the warfarin-treated group after thrombolysis even after multivariate adjustment for the relevant covariates age, atrial fibrillation, initial stroke severity by the National Institutes of Health Stroke Scale, and INR [4]. A large observational study assessing the influence of antithrombotic pretreatment on stroke severity in patients with ischemic stroke and atrial fibrillation found no difference in the frequency of spontaneous secondary intracranial hemorrhage in the warfarin-treated group compared to the group not receiving anticoagulant treatment prior to admission [5]. Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke
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