Matthew Edwardson, MD

Wang X, Fan X, Yu Z, Liao Z, Zhao J, Mandeville E, et al. Effects of Tissue Plasminogen Activator and Annexin A2 CombinationTherapy on Long-Term Neurological Outcomes of Rat Focal Embolic Stroke. Stroke. 2014

Like many stroke neurologists, I love administering IV-TPA and can attest to reduced disability in treated patients. Yet there is nothing more disheartening than the few patients who experience significant hemorrhagic conversion. What if there was a way to reduce these hemorrhage rates while simultaneously increasing the likelihood of clot lysis resulting in better long-term outcomes? Wang and colleagues describe exactly that in a rat stroke model treated with combination low-dose IV-TPA and annexin A2.



Annexin A2 is a cell-surface protein that forms a complex with plasminogen and TPA. This complex is > 60 times more efficient at converting plasminogen to plasmin than equivalent doses of TPA alone. TPA increases the likelihood of hemorrhagic conversion partly because it contributes to blood brain barrier disruption. The combination of TPA and annexin A2 may allow clinicians to deliver lower doses of TPA – thereby reducing ICH risk – while at the same time improving recanalization rates.

The authors randomized 60 rats to high-dose TPA (10mg/kg – equivalent to standard 1mg/kg dose in humans) vs. low-dose TPA (5mg/kg) + annexin A2 three hours after middle cerebral artery occlusion. A prior study showed reduced hemorrhage with combination low-dose TPA and annexin A2 in comparison to high-dose TPA. The current study was focused on long-term outcome and showed significantly reduced infarct size, neurologic deficits, and higher density of cerebrovascular tissue in the peri-infarct zone in the low-dose TPA + annexin A2 group 1 month post-stroke.

This study provides evidence of good long-term outcomes following combination low-dose TPA and annexin A2 therapy in a rat stroke model, a significant step prior to translation into human trials. One of the outcomes – density of cerebrovascular tissue in the peri-infarct zone – may be confounded by infarct size. Rats treated with combination low-dose TPA and annexin A2 ended up with smaller infarcts. Perhaps the larger area of reversed ischemia in this group promoted endogenous tissue remodeling as opposed to any neuroprotective effect of annexin A2. In any case the important point, well demonstrated in this study, is that annexin A2 did not worsen post-stroke tissue remodeling. Low-dose TPA combined with annexin A2 holds great promise. I am very excited to see this studied in human subjects, but first we must keep in mind the multitude of failed prior translational neuroprotection trials for stroke. The authors would do well to complete the remaining STAIR committee recommendations before translation – most importantly confirming the findings in an independent laboratory.