title: Platelet rich clots are resistant to lysis by thrombolytic therapy in a rat model of embolic stroke.
abstract: BACKGROUND
  Early recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. Microbubble-enhanced sonothrombolysis is a promising therapy to improve recanalization rates and reduce the time to recanalization. Testing any thrombolytic therapy requires a model of thromboembolic stroke, but to date these models have been highly variable with regards to clot stability. Here, we developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA). This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis.
  
  
  METHODS
  In Study 1 we investigated spontaneous recanalization rates of PRC in vivo over 4 hours and measured infarct volumes at 24 hours. In Study 2 we investigated tPA-mediated thrombolysis and microbubble-enhanced sonothrombolysis in this model.
  
  
  RESULTS
  Study 1 demonstrated stable occlusion out to 4 hours in 5 of 7 rats. Two rats spontaneously recanalized at 40 and 70 minutes post-embolism. Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7). In Study 2, recanalization was not observed in any of the groups post-treatment.
  
  
  CONCLUSIONS
  Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction. These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis. This resistance of platelet rich clots to enhanced thrombolysis may explain recanalization failures clinically and should be an impetus to better clot-type identification and alternative recanalization methods.
authors: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors: Amelia J
authors: AJ
authors: Tomkins
authors: Heart and Brain Research Group, Justus-Liebig-University, Giessen and Kerckhoff Clinic, Bad Nauheim, Germany ; Department of Neurology, Justus-Liebig-University, Giessen, Germany ; Department of Cardiac Surgery, Kerckhoff Clinic, Bad Nauheim, Germany.
authors: Nadine
authors: N
authors: Schleicher
authors: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors: Lucy
authors: L
authors: Murtha
authors: Department of Neurology, Justus-Liebig-University, Giessen, Germany.
authors: Manfred
authors: M
authors: Kaps
authors: Hunter New England Local Health District, Newcastle, Australia ; School of Medicine and Public Health, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors: Christopher R
authors: CR
authors: Levi
authors: Department of Neurology, Justus-Liebig-University, Giessen, Germany ; Sana Regio Klinkum, Pinneberg, Germany ; Department of Neurology, University Hospital Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Max
authors: M
authors: Nedelmann
authors: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia ; Hunter New England Local Health District, Newcastle, Australia.
authors: Neil J
authors: NJ
authors: Spratt
keywords: Embolic Stroke; Microbubbles; Platelet Rich Clot; Rat; Sonothrombolysis; Thrombolysis; Ultrasound
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