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Thrombolytic activity of BB‐10153, a thrombin‐activatable plasminogen
Author(s) -
COMER M. B.,
CACKETT K. S.,
GLADWELL S.,
WOOD L. M.,
DAWSON K. M.
Publication year - 2005
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2004.01087.x
Subject(s) - plasmin , thrombin , plasminogen activator , tissue plasminogen activator , in vivo , pharmacology , heparin , chemistry , medicine , hemostasis , thrombolysis , fibrinogen , bolus (digestion) , thrombin time , endocrinology , platelet , biochemistry , partial thromboplastin time , myocardial infarction , biology , enzyme , microbiology and biotechnology
Summary. Background: BB‐10153 is an engineered variant of human plasminogen, modified to be activated to plasmin by thrombin. Thrombin‐activatable plasminogen was designed as a novel thrombolytic agent which would persist in the blood as a prodrug and be activated to plasmin only at fresh or forming thrombi by the thrombin that is tightly localized there. We previously described the construction of several thrombin‐activatable plasminogens and their in vitro clot lysis activity. Objectives and methods: The current study was an examination of the thrombolytic properties of BB‐10153 in vivo ; comparison was made with tissue‐type plasminogen activator (t‐PA) in a femoral artery copper coil thrombosis model in the anesthetized dog and rabbit. Heparin was not coadministered so that the fundamental activity of the agents could be compared. Results: BB‐10153, administered as an intravenous bolus of 5 mg kg −1 in the dog and 10 mg kg −1 in the rabbit, produced a comparable incidence of reperfusion to 3 mg kg −1 t‐PA. Reocclusion at these doses occurred in 4/4 dogs and 5/7 rabbits treated with t‐PA and in 2/6 dogs and 0/10 rabbits treated with BB‐10153. There was no reocclusion in three dogs dosed with 10 mg kg −1 BB‐10153. BB‐10153 did not affect plasma α 2 ‐antiplasmin levels or the bleeding time, whereas 3 mg kg −1 t‐PA caused marked depletion of α 2 ‐antiplasmin and fibrinogen and increased the bleeding time. The plasma half‐life of BB‐10153 was 3–4 h. Conclusions: The long half‐life and thrombus‐selective thrombolytic activity of BB‐10153 might allow it to overcome the bleeding and reocclusion shortfalls in the performance of current thrombolytics.