The plasmin heavy chain-urokinase conjugate: a specific thrombolytic agent.
Low molecular weight urokinase (LMW-UK) was coupled to the heavy chain of plasmin to make it able to bind to fibrin. The purified conjugate (PHC-UK conjugate), which consisted of equimolar concentrations of each starting material had a molecular weight of 93,600, bound tightly to fibrin-monomer-Sepharose and was not washed off with 1 M NaCl, but was eluted specifically with epsilon-amino caproic acid. The conjugate showed higher fibrinolytic activity than HMW-UK. A control conjugate prepared by coupling human serum albumin to LMW-UK (HSA-UK conjugate) showed the same fibrinolytic activity as HMW-UK. The half-lives of these two conjugates in rabbits were about 3 times that of HMW-UK. In an experimental pulmonary embolism model in rabbits, the PHC-UK conjugate showed about 10 times higher thrombolytic activity than HMW-UK, while the HSA-UK conjugate showed similar thrombolytic activity as HMW-UK, and moreover caused severe systemic fibrinogen breakdown. Thus the significant increase in thrombolytic activity after injection of PHC-UK conjugate into rabbits may be due to its newly acquired fibrin binding activity, and not to increase in its half-life. It is concluded that the PHC-UK conjugate may be useful in treatment of thrombosis.
D000818:Animals; D001822:Body Burden; D005337:Fibrin / Q000378:metabolism; D005341:Fibrinolysin / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy; D014568:Urokinase-Type Plasminogen Activator / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D008301:Maleimides; C051958:plasmin heavy chain-urokinase conjugate; C043592:maleimide; D005337:Fibrin; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator