Compositions and methods for treating vascular disease

Abstract

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.

1 . A method comprising:
 a) providing:
 i) a patient exhibiting symptoms associated with a vascular disorder, and 
 ii) a medium comprising Annexin A2 and tissue plasminogen activator (tPA); and 
   b) administering said medium to said patient under conditions such that said symptoms are reduced.   
     
     
         2 . The method of  claim 1 , wherein said vascular disorder is selected from the group consisting of stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis and intracerebral hematoma. 
     
     
         3 . The method of  claim 1 , wherein said Annexin A2 and said tPA have a dose ratio of 2:1. 
     
     
         4 . The method of  claim 1 , wherein said medium comprises a carrier. 
     
     
         5 . The method of  claim 4 , said Annexin A2 and said tPA are attached to said carrier. 
     
     
         6 . The method of  claim 1 , wherein said carrier is selected from the group consisting of a liposome and a microparticle. 
     
     
         7 . The method of  claim 1 , wherein said medium is a liquid. 
     
     
         8 . The method of  claim 7 , wherein said administering is intravenous. 
     
     
         9 . The method of  claim 1 , wherein said patient is a human. 
     
     
         10 . The method of  claim 1 , wherein said patient is a non-human. 
     
     
         11 . A method comprising:
 a) providing:
 i) a patient exhibiting symptoms associated with a recently incurred stroke, 
 ii) a medium comprising Annexin A2 and tissue plasminogen activator (tPA), wherein said Annexin A2 and said tPA have a dose ratio of 2:1; 
   and,   b) administering said medium to said human subject under conditions such that said symptoms are reduced.   
     
     
         12 . The method of  claim 11 , wherein said administering occurred less than three hours after said stroke. 
     
     
         13 . The method of  claim 11 , wherein said administering occurred less than six hours after said stroke. 
     
     
         14 . The method of  claim 11 , wherein said administering occurred less than twelve hours after said stroke. 
     
     
         15 . The method of  claim 11 , wherein said tPA dose is at least two-fold lower than the currently recommended dose. 
     
     
         16 . The method of  claim 11 , wherein said tPA dose is at least three-fold lower than the currently recommended dose. 
     
     
         17 . The method of  claim 11 , wherein tPA dose is at least four-fold lower than the currently recommended dose. 
     
     
         18 . A medium comprising Annexin A2 and tissue plasminogen activator (tPA). 
     
     
         19 . The medium of  claim 18 , wherein said Annexin A2 and said tPA have a dose ratio of 2:1. 
     
     
         20 . The medium of  claim 18 , wherein said medium further comprises a carrier. 
     
     
         21 . The medium of  claim 20 , wherein said Annexin A2 and said tPA are attached to said carrier. 
     
     
         22 . The medium of  claim 20 , wherein said carrier comprises a liposome population. 
     
     
         23 . The medium of  claim 20 , wherein said carrier comprises a microparticle population. 
     
     
         24 . The medium of  claim 20 , wherein said medium comprises a liquid. 
     
     
         25 . A kit comprising a medium comprising Annexin A2 and tissue plasminogen activator (tPA). 
     
     
         26 . The kit of  claim 25 , wherein said medium further comprises a carrier. 
     
     
         27 . The kit of  claim 26 , wherein said tPA and said Annexin A2 are attached to said carrier. 
     
     
         28 . The kit of  claim 25 , wherein said kit further comprises a sheet of instructions regarding administration of said medium following a vascular disorder. 
     
     
         29 . The kit of  claim 28 , wherein said vascular disorder is selected from the group consisting of stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis and intracerebral hematoma. 
     
     
         30 . The kit of  claim 25 , wherein said kit further comprises a syringe. 
     
     
         31 . The kit of  claim 25 , wherein said kit further comprises an intravenous catheter. 
     
     
         32 . The kit of  claim 31 , wherein said kit further comprises an intravenous drip bag capable of fluid communication with said intravenous catheter.