Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke

Abstract

This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

The importance of selected markers of inflammation and blood-brain barrier damage for short-term post-stroke prognosis

“…[38,39] We obtained a positive correlation between the presence of NSE and a worse neurological status on the first day, and between S100B and a poor status on the first and 30th day of stroke, which is consistent with the observations reported by other authors. [15,[40][41][42] We observed a positive correlation between the concentrations of NSE and S100B.…”

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

“…Thus, patients who can receive rt-PA therapy are still limited (3.4–5.2% of all patients with acute ischemic stroke) and this is largely due to the risk of R/I, particularly the complication of cerebral hemorrhage which can worsen outcome and increase mortality ( 268 ). tPA is a serine protease and can thus promote ECM damage which can lead to HTf ( 269 ). Hence, combined therapy with agents that suppress inflammatory molecules, thus preventing BBB disruption and downstream effects such as edema and hemorrhage seem viable approaches.…”

Exosomes Derived From CircAkap7-Modified Adipose-Derived Mesenchymal Stem Cells Protect Against Cerebral Ischemic Injury

“…Although recent studies on the pathogenesis of ischemic stroke have resulted in improvements in long-term prognoses, current treatments for acute cerebral ischemia are still largely based on the intravenous administration of recombinant tissue plasminogen activator ( Prabhakaran et al, 2015 ). Due to the short therapeutic time window for this approach, as well as medication contraindications, fewer than 5% of stroke patients undergo this treatment, and risk bleeding outcomes ( Kanazawa et al, 2017 ). The clinical research into neuroprotective drugs for stroke has so far been unsuccessful ( Chamorro et al, 2016 ).…”