Human blood-derived products having decreased fibrinolytic activity and uses thereof in hemostatic disorders

Abstract

The present invention provides therapeutic products with decreased fibrinolytic activity of t-PA-deficient and/or plasminogen-deficient blood products, as well as compositions, kits and methods using the same in treating bleeding associated with hereditary or acquired bleeding disorders. The invention further provides extracorporeal apparatus for blood or blood products Plasmapheresis aimed to prevent or treat bleeding disorders.

1 . An extracorporeal apparatus for blood and blood product pheresis, wherein said apparatus comprises or is coated, at least in part, by at least one molecule that specifically binds tissue plasminogen activator (tPA) and plasminogen. 
     
     
         2 . The extracorporeal apparatus according to  claim 1 , wherein the molecule that specifically binds tPA and plasminogen is at least one of: 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid), ϵ-amino caproic acid, lysine, anti-plasminogen antibodies and anti-tPA antibodies. 
     
     
         3 . The extracorporeal apparatus according to  claim 1 , wherein said apparatus comprises or is coated, at least in part, by tranexamic acid that specifically binds at least one of tPA and plasminogen. 
     
     
         4 . The extracorporeal apparatus according to  claim 1 , wherein said at least one molecule that specifically binds tPA and plasminogen is provided in a filter comprising said at least one molecule that specifically binds tPA and plasminogen, optionally linked to a solid support. 
     
     
         5 . The extracorporeal apparatus according to  claim 1 , wherein said apparatus is adapted for affinity depletion procedure specific for t-PA and plasminogen from a blood and/or blood-derived product. 
     
     
         6 . The extracorporeal apparatus according to  claim 5 , wherein said depletion procedure results in a blood and/or blood-derived product that has a reduced fibrinolytic activity. 
     
     
         7 . The extracorporeal apparatus according to  claim 6 , wherein said blood or a blood-derived product has decreased R-value in thromboelastography (TEG) analysis, as compared to blood or blood-derived product not subjected to said depletion procedure. 
     
     
         8 . The extracorporeal apparatus according to  claim 1 , wherein said apparatus is, or comprises at least one apheresis unit for blood and blood product pheresis. 
     
     
         9 . The extracorporeal apparatus according to  claim 1 , the extracorporeal apparatus is a cardiopulmonary bypass machine (CPB), or a plasmapheresis machine. 
     
     
         10 . An apheresis unit for blood and blood product pheresis, adapted for affinity depletion procedure specific for t-PA and plasminogen, wherein said affinity-depletion procedure uses a molecule that specifically binds tPA and plasminogen, optionally, wherein the molecule that specifically binds tPA and plasminogen is at least one of: 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid), ϵ-amino caproic acid, lysine, anti-plasminogen antibodies and anti-tPA antibodies. 
     
     
         11 . The apheresis unit according to  claim 10 , wherein said unit comprises or is coated, at least in part, by tranexamic acid that specifically binds at least one of tPA and plasminogen. 
     
     
         12 . The apheresis unit according to  claim 10 , wherein said at least one molecule that specifically binds tPA and plasminogen is provided in a filter comprising said at least one molecule that specifically binds tPA and plasminogen, optionally linked to a solid support. 
     
     
         13 . The apheresis unit according to  claim 10 , wherein said unit is adapted for affinity depletion procedure specific for t-PA and plasminogen from a blood and/or blood-derived product. 
     
     
         14 . The apheresis unit according to  claim 13 , wherein said depletion procedure results in a blood and/or blood-derived product that has a reduced fibrinolytic activity. 
     
     
         15 . The apheresis unit according to  claim 14 , wherein said blood or a blood-derived product has decreased R-value in thromboelastography (TEG) analysis, as compared to blood or blood-derived product not subjected to said depletion procedure. 
     
     
         16 . A method for performing an extracorporeal procedure in a subject in need thereof, the method comprising the steps of:
 (i) transferring blood of said subject into an extracorporeal apparatus, as defined by  claim 1 ;   (ii) subjecting said blood to affinity depletion procedure specific for tPA and plasminogen, wherein said depletion is performed before, during or after blood is transferred into and out-off said apparatus, thereby obtaining an extracorporeal tPA-deficient and plasminogen deficient blood and/or blood-derived product of said subject; and optionally   (iii) returning the t-PA and plasminogen-deficient blood or plasma obtained in step (ii) to said subject.   
     
     
         17 . The method according to  claim 16 , wherein said affinity depletion procedure of tPA and plasminogen is performed by contacting said blood with at least one molecule that specifically binds at least one of tPA and/or plasminogen, optionally, wherein the molecule that specifically binds tPA and plasminogen is at least one of: 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid), ϵ-amino caproic acid, lysine, anti-plasminogen antibodies and anti-tPA antibodies. 
     
     
         18 . A method for the treatment, amelioration, or inhibition of bleeding in a subject having a hemostatic disorder or any bleeding or pathologic condition associated therewith, by administering to said subject a therapeutically effective amount of a blood and/or blood-derived product that was subjected to affinity depletion procedure specific for t-PA and plasminogen, and display a reduced fibrinolytic activity, wherein said affinity depletion procedure is performed using the apparatus according to  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein said affinity depletion procedure comprises the steps of:
 (i) transferring blood of said subject into said extracorporeal apparatus;   (ii) subjecting said blood to affinity depletion procedure specific for tPA and plasminogen, wherein said depletion is performed before, during or after blood is transferred into and out-off said apparatus, thereby obtaining an extracorporeal tPA-deficient and plasminogen deficient blood and/or blood-derived product of said subject; and   (iii) returning the t-PA and plasminogen-deficient blood or plasma obtained in step (ii) to said subject.   
     
     
         20 . The method according to  claim 18 , wherein said hemostatic disorder is hereditary or acquired bleeding disorder, optionally wherein at least one of:
 (a) said hereditary hemostatic disorder is a disorder resulting from at least one of deficiency in at least one coagulation factor and undefined tendency to bleeding;   (b) said acquired hemostatic disorder is at least one of surgery-induced bleeding, trauma-induced bleeding, acute gastrointestinal bleeding, bleeding associated with burns, hemorrhagic stroke, lung injury due to emphysema and Chronic Obstructive Pulmonary Disease (COPD), bleeding associated with childbirth and bleeding resulting from fibrinolytic or thrombolytic therapy.