The use of tPA to treat hemorrhagic transformation, neurotoxicity has been limited to short treatment time windows because a high dose of tPA required to generate sufficient amounts of the enzyme plasmin for clot lysis. The present invention combines tPA with recombinant Annexin A2 resulting in thrombolysis without hemorrhagic transformation at delayed times after stroke. This embodiment allows the administration of a lower, non-neurotoxic, tPA dose. Our results suggest this novel combination for stroke therapy may greatly improve both efficacy and safety, and prolong tPA therapeutic time window.