Towards enhanced thrombolysis in stroke

Dr Simone Schoenwaelder, Heart Research Institute & University of Sydney.

Pharmacological fibrinolysis of arterial thrombi by recombinant tissue plasminogen activator (rtPA) remains the mainstay treatment of ischemic stroke. Unfortunately, the extent of arterial recanalization and cerebral microvascular perfusion remains suboptimal in many stroke patients, therefore there is a pressing need to develop safe and effective adjuvant therapies that enhance the thrombolytic potential of rtPA. Progress in this area would be assisted by the development of preclinical stroke models that allow analysis of both recanalization and reperfusion during thrombolytic therapy and to correlate this with infarct volumes and stroke outcomes.

We have established an in situ carotid artery thrombo(ly)sis (iCAT) model that enables real-time assessment of large artery recanalization and cerebral reperfusion in mice. Real-time ultrasound doppler monitoring and histological analysis of carotid arteries confirmed that occlusive thrombi were partially lysed with rtPA alone, with further enhancement of thrombolysis when rtPA was combined with the platelet GPIIb-IIIa inhibitor integrilin, or the anticoagulants, hirudin and agatroban. Ipsilateral carotid artery occlusion was combined with transient stenosis of the contralateral carotid artery to cause controlled hypoperfusion within the middle cerebral artery territory, at 6 and 24-hours, and was associated with functional deficits in recovered mice. Real-time monitoring of perfusion with laser doppler flowmetry greatly facilitated the reproducibility and predictability of the iCAT model, whilst also reducing surgical mortality. The iCAT model generates unilateral cerebral penumbra and infarction following extracranial thrombotic occlusion, and allows for real-time monitoring of recanalization and reperfusion. This preclinical model should be valuable in enabling assessment of the impact of novel adjuvant thrombolytic therapies on large vessel recanalization, cerebral perfusion, penumbral salvage and functional stroke outcomes.

Dr Schoenwaelder completed doctoral studies at Monash University (1996), followed by several postdoctoral years at the University of North Carolina, Chapel Hill (USA) as an NHMRC CJ Martin Fellow in the laboratory of Professor Keith Burridge. Upon completion of her postdoctoral studies in 1999, Simone returned to Australia as an NHMRC RD Wright and Monash University Logan Research Fellow, joining the Australian Centre for Blood Diseases (ACBD). In 2015, Simone relocated to her current position at the Heart Research Institute and University of Sydney, NSW. In her current position, she is an Associate Professor of Research at the Heart Research Institute and Charles Perkins Centre at the University of Sydney (NSW), Associate Director of Research Management and Education of the Heart Research Institute, honorary Associate Professor in the Department of Physiology, University of Sydney, and Adjunct Associate Professor at Monash University (Victoria). Her research focusses on advancement in our understanding on the role of platelets in arterial thrombosis, through fundamental discovery research.