Annexin A2

Abstract

Abstract-Hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and the short treatment time window comprise major challenges for thrombolytic therapy. Improving tissue plasminogen activator therapy has become one of the highest priorities in the stroke field. Recent efforts have been aimed at identifying new strategies that might enhance the thrombolytic efficacy of tissue plasminogen activator at the same time as reducing its associated complications related to hemorrhage and neurotoxicity. We believe that the combination of low-dose tissue plasminogen activator with recombinant annexin A2 (a tissue plasminogen activator and plasminogen coreceptor) might constitute a promising approach. Our pilot study using a focal embolic stroke model in rats supports this hypothesis.

Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment- associated hemorrhage and improves recovery in rat embolic focal stroke

“…We might speculate that in addition to the reduction in tPA-associated ICH transformation, the lower tPA dose and formed rA2-tPA complex might limit tPA brain penetration-associated neuronal excitotoxicity [22], and rA2 might bind and neutralize angiostatin (one of tPA-plasminogen converting products)-associated endothelial toxicity [23]. Ultimately, decreased hemorrhagic brain damage and fewer neurovascular side effects of the combination treatment might translate into better vascular remodeling and improved long-term neurological outcome [4]. …”

“…However, the short therapeutic time window, ICH transformation, poor thrombolytic perfusion rate, and neurotoxicity comprise major limitations to its use [1–3]. Annexin A2 is a cell-surface protein that can forma triple complex with tPA and plasminogen, which increases the catalytic efficiency of tPA, enabling it to convert plasminogen to plasmin more efficiently in about 60 fold than same amount of tPA alone in vitro [4]. However, clinicallygiving large amount of tPA alone but without fibrinolytic assembly of the tPA-annexin A2-plasminogen complex formation, makes tPA converting plasminogen to plasmin inefficiently, which may be partially responsible for the shortcomings of tPA reperfusion therapy [4].…”

“…Annexin A2 is a cell-surface protein that can forma triple complex with tPA and plasminogen, which increases the catalytic efficiency of tPA, enabling it to convert plasminogen to plasmin more efficiently in about 60 fold than same amount of tPA alone in vitro [4]. However, clinicallygiving large amount of tPA alone but without fibrinolytic assembly of the tPA-annexin A2-plasminogen complex formation, makes tPA converting plasminogen to plasmin inefficiently, which may be partially responsible for the shortcomings of tPA reperfusion therapy [4]. Our previous experiments have shown that low-dose tPA combining with its “amplifier” rA2 is more effective than conventional tPA alone when treated within 3 hours after focal embolic stroke in rats [5–7].…”

Annexins – insights from knockout mice

“…AnxA2 isolated from mice fed a high methionine diet failed to bind tPA and activate plasminogen, while intravenous injection of recombinant AnxA2 partially restored angiogenetic activity in this mouse model . In ischemic cerebral disease, recombinant AnxA2 may serve as an adjunct drug to amplify tPA-mediated thrombolysis to prevent stroke (Fan et al, 2010). However, although inhibition of plasmin generation has therapeutic potential in atherosclerosis, crossing the AnxA2 -/-mice into an apoEdeficient background did not reduce lesion development compared to the control apoE KO animals (Hedhli et al, 2012).…”

2013 Thomas Willis Award Lecture

“…However, treatment effects may sometimes be modest, and narrow time windows limit the number of patients who can be treated. Therefore, it is logical for ongoing research to focus on strategies that can amplify reperfusion 8 or develop new biomarker methods for finding patients who are most responsive to therapy. 9–12 But beyond these efforts to normalize blood flow or restore blood vessel integrity, it has been difficult to find effective treatments that target fundamental cell death processes in injured neurons.…”