Abstract
Risk of hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and a short treatment time window comprises major challenges for tissue plasminogen activator (tPA) thrombolytic stroke therapy. Improving tPA therapy has become one of the highest priorities in the stroke field. This mini review article focuses on our recent efforts aimed at evaluating a novel combination approach of low-dose tPA plus recombinant annexin A2 (rA2, a tPA, and plasminogen co-receptor), which might enhance tPA thrombolytic efficacy, while reducing its associated complications related to intracerebral hemorrhagic transformation. Results of our experimental studies using a focal embolic stroke model in rats support the feasibility of the combination approach and suggest the potential for successful clinical translation.
Highlights
By translating the tissue plasminogen activator (tPA) fibrinolytic assembly into tPA therapy development, we hypothesized that combining recombinant annexin A2 protein will lower the required dose of tPA for reperfusion, while enhancing thrombolytic efficacy, and attenuating intracerebral hemorrhagic (ICH) transformation
In a focal embolic stroke model in rats, when animals were treated intravenously 2 h after initiation of ischemia, the 25–50% lower-dose tPA plus recombinant annexin A2 protein (rA2) combination was as effective as the standard high-dose tPA alone in restoring perfusion and reducing infarct size (Zhu et al, 2010)
Improved reperfusion by the combination was confirmed by MRI analysis in focal embolic stroke of rats (Walvick et al, 2011). We extended these promising findings by asking whether the benefits of tPA plus rA2 combination therapy can be sustained for long-term neurological outcomes
Summary
By stimulating thrombolysis and rescuing the ischemic brain via restoring blood flow, intravenous administration of recombinant tissue plasminogen activator (tPA) remains the most effective intervention with FDA approval for emergency treatment of stroke (Whiteley et al, 2014). Other thrombolytic agents are being tested, none has been established as effective or as a replacement for tPA (Wang et al, 2004, 2008; Adams et al, 2007). A randomized phase III trial, ECASS III, designed to test treatment with tPA at 3–4.5 h, showed improved clinical outcomes for ischemic patients with thrombolytic treatment (Hacke et al, 2008). The benefits of thrombolysis are, still heavily dependent on the treatment time, and tPA remains associated with increased risk of intracranial hemorrhage and reperfusion injury (Hacke et al, 2008). It has been clinically prioritized to seek combination therapies that may extend the therapeutic window, reduce tPA-associated hemorrhagic transformation, and improve thrombolytic efficacy (Wang et al, 2004, 2008; Whiteley et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
