Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke

Abstract

Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke.

Keywords: Blood; Brain barrier; Hemorrhagic transformation; Ischemic stroke; Tissue plasminogen activator.

Fig. 1

Mechanisms underlying blood–brain barrier damage induced by rt-PA in ischemic stroke. I/R ischemic/reperfusion, tPA tissue-type plasminogen activator, ROS reactive oxygen species, RNS reactive nitrogen species, MMP matrix metalloproteinase, TJ tight junction, HT hemorrhagic transformations, CCR2 C–C chemokine receptor type 2, CXCL3 C-X-C motif ligand 3, LRP lipoprotein receptor-related protein, TGF-β1 transforming growth factor-beta 1

Fig. 2

The cellular mechanism of HT after ischemic stroke treated by rt-PA. I/R ischemic/reperfusion, tPA tissue-type plasminogen activator, ROS reactive oxygen species, RNS reactive nitrogen species, MMP matrix metalloproteinase, VEGF vascular endothelial growth factor, SUR1-TRPM4 sulfonylurea receptor 1-transient receptor potential meastatin 4, PAR1 protease activated receptor 1, HMGB1 High-mobility group box 1, TLR4 Toll-Like Receptor 4, HIF hypoxia inducible factor 1

Fig. 3

Potential biomarkers and clinical risk factors of hemorrhagic transformation in patients treated by rt-PA after ischemic stroke. HT hemorrhagic transformations, UA uric acid, c-Fn cellular fibronectin, MMP-9 matrix metalloproteinase-9, VEGF vascular endothelial growth factor, VAP-1 vascular adhesion protein-1, SSAO semicarbazide-sensitive amine oxidase, CMBs cerebral microbleeds, CAA cerebral amyloid angiopathy