Optimal strategy for effective dissolution of the thrombus in thrombolysis models

Abstract

Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is a proven therapy for acute ischemic stroke. However, its efficacy is limited due to its relatively low potency in dissolving thrombus, as well as the likelihood for hemorrhagic transformation and re-occlusion. During thrombolytic treatment with rt-PA, the thrombus undergoes dynamic changes. Lysis of the thrombus alternates with re-growth of the thrombus, leading to re-occlusion and platelets play major roles in this process. We investigated whether the combined use of aggrastat or atorvastatin can potentiate the efficacy of rt-PA using a ferric chloride-induced carotid arterial thrombosis model in mice and an in vitro model using rotation thromboelastometry (ROTEM) and platelet aggregometry. Infusion of aggrastat immediately after the end of rt-PA infusion resulted in improved efficacy in preventing re-occlusion in mice treated with rt-PA alone. However, when aggrastat was administrated to mice simultaneously at the time of rt-PA bolus infusion, it did not significantly improve the thrombolytic effects. Compared with the group treated with rt-PA only, the group treated with concomitant atorvastatin and rt-PA showed improved effects in terms of shorter time to initiation of lysis or recanalization and longer persistent recanalization of the blood flow. By ROTEM assay, clot firmness at 20, 25, and 30 minutes was lower in the group treated with a combination of rt-PA and atorvastatin than in the control group. Likewise, in terms of the lysis parameter, the EX lysis index at 30 minutes was shorter in the group treated with concomitant atorvastatin and rt-PA, which implies that clot lysis was greater at 30 minutes. However, there was no significant difference in the variables of FIBTEM. These results suggest that adding atorvastatin to rt-PA produces a faster thrombolytic response through inhibition of the platelet-related pathway. Platelet aggregometry confirmed that atrovastatin inhibited platelet aggregation as maximal aggregation values and the area under curve were significantly lower in the atorvastatin-treated group. However, lipid profiles were not different between the two groups, which suggests that these effects were not due to the lipid lowering effects of atorvastatin. Our results suggest that rt-PA treatment can be improved by adjuvant use of aggrastat or atorvastatin, and that their effectiveness is due to their antiplatelet actions.