Novel approaches to enhance the thrombolytic potential of tissue plasminogen activator (tPA) therapy in stroke

Abstract

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) remains the primary pharmacological therapy for acute ischaemic stroke. Despite some significant clinical benefit at three months, rtPA-mediated recanalisation rates remain suboptimal in over 50% of patients receiving this therapy, and cerebral reperfusion is not always achieved with arterial reopening. The aim of these doctoral studies was to investigate novel adjunctive antithrombotic approaches to enhance rtPA-mediated large artery recanalisation and improve cerebral perfusion in a mouse model of stroke. Initial studies focused on the development of the in situ carotid artery thrombo(ly)sis (iCAT) model, the first mouse model of electrolytic-induced carotid artery thrombosis and graded unihemispheric hypoperfusion leading to cerebral infarction. This model allows for the simultaneous real-time assessment of recanalisation, cerebral perfusion and end-organ damage. Extensive characterisation of the iCAT model validated its suitability for the assessment of thrombolytic and adjunctive antithrombotic therapy. Combining rtPA with the anticoagulant therapy (Argatroban) enhanced recanalisation (41.9% vs 22.2% rtPA alone) and significantly improved cerebral perfusion (laser speckle contrast imaging), leading to a moderate reduction in infarct volumes (TTC) at 24 hours. Collectively, these studies present a novel mouse model for the real-time assessment of recanalisation, reperfusion and end-organ damage.