Thrombolytic activity of BB-10153, a thrombin-activatable plasminogen

Abstract

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 α2‐antiplasmin levels or the bleeding time, whereas 3 mg kg−1 t‐PA caused marked depletion of α2‐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.

Thrombin‐Responsive Transcutaneous Patch for Auto‐Anticoagulant Regulation

“…Moreover, as presented in the skin tissues stained with the in situ TUNEL assay, obvious cell apoptosis occurred in the skin treated with HP MN, while no cell death was observed in the skin treated with the TR-HAHP MN, NR-HAHP and pure HA MN ( Figure 4e ). Finally, the TR-HAHP MN avoided unwanted bleeding due to the locally generated, and considerably lower levels of activated thrombin at the sealing major wounds, [28] which could not be sensed by the MNs in the treated subcutaneous tissue ( Figure S11 ).…”

Self-Titrating Anticoagulant Nanocomplexes That Restore Homeostatic Regulation of the Coagulation Cascade

“…This finding may be due to the fact that sealing major wounds is largely dependent on platelet activation and plug formation, a process that requires considerably lower levels of activated thrombin than during thrombus formation. 46,47 Taken together, these data showed that nanoSTATs circulate in an inactive form, veiling heparin activity and decreasing the risk of bleeding.…”

Leukocyte count affects expression of reference genes in canine whole blood samples

“…Anticoagulant therapy has been tested extensively in canine cardiac surgery models [11,12]. Also the pathogenesis and therapy of acquired disorders of hemostasis such as disseminated intravascular coagulation[13], thrombosis [14,15], and hemolytic uremic syndrome [16] have been investigated in canine models.…”