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

Abstract

We previously have shown that tissue type plasminogen activator (tPA) in combination with its receptor annexin A2 (rA2) protein significantly improved tPA thrombolytic efficacy. In this study we aimed to examine the therapeutic effects of the combination when treated at delayed 4-hour window after stroke compared to standard conventional tPA alone in an embolic focal stroke rat model. We compared effects of intravenous tPA alone (10 mg/kg) versus a combination of low-dose tPA (5 mg/kg) plus 10 mg/kg rA2. Totally 152 rats were used. Our results showed that: (1) at 24 h after stroke, the combination slightly reduced brain infarction compared to saline (9.2% reduction), and tPA (7.4% reduction), although the reductions did not reach statistical significance; while the combination significantly reduced (22.2% reduction) the conventional tPA-elevated intracerebral hemorrhagic (ICH) transformation; (2) at 7 days after stroke, the combination significantly attenuated conventional tPA alone-elevated iron deposition at peri-lesion area (68.2% reduction); (3) at 28 days after stroke, the combination significantly improved performance of adhesive tape-removal test, which was accompanied by a significantly higher micro vessel density at peri- infarct areas compared to conventional tPA alone group.In conclusion, compared to conventional tPA alone, when treated at delayed 4-hour after stroke, the combination of low-dose tPA plus rA2 therapy provides a safer profile by lowering risk of ICH transformation and improves neurological function recovery after stroke.

Keywords: Annexin A2; Combination thrombolytic therapy; Embolic focal stroke; Intracerebral hemorrhagic transformation; Long term neurological outcomes; Tissue plasminogen activator.