Fibrin specific thrombolysis by two-chain urokinase-type plasminogen activator cleaved after arginine 156 by thrombin.
Scu-PA was cleaved by thrombin after arginine-156 to yield a two-chain molecule with low amidolytic activity and resistance to cleavage by plasmin. 125I-fibrin-labeled clots were dissolved in vitro by thrombin-cut scu-PA, but only at concentrations 10- to 50-fold greater than that needed for scu-PA. Three hours of incubation produced 100, 80, and 31% lysis with 100, 50, and 25 micrograms/ml thrombin-cut scu-PA. Thrombin-cut scu-PA, scu-PA, and tcu-PA yielded linear dose responses in the rabbit jugular venous thrombosis model. The dose required to reach 40% lysis was 2 mg/kg for scu-PA, 3 mg/kg for tcu-PA, and 4 mg/kg for thrombin-cut scu-PA. No significant consumption of fibrinogen or alpha 2-antiplasmin levels was observed with thrombin-cut scu-PA while the level of fibrinogen and alpha 2-antiplasmin decreased to about 50 and 40%, respectively, with scu-PA and to less than 10% of baseline with tcu-PA. Thus, while less potent than scu-PA, thrombin-cut scu-PA appears to be a more fibrin-specific thrombolytic agent than scu-PA.
Abercrombie
D M
DM
Department of Molecular Genetics and Biochemistry, Collaborative Research Inc., Bedford, Massachusetts.
Buchinski
B
B
Salvato
K A
KA
Vovis
G F
GF
Stump
D C
DC
Broeze
R J
RJ
D000577:Amides / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine; D004591:Electrophoresis, Polyacrylamide Gel; D005343:Fibrinolytic Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D007601:Jugular Veins; D008969:Molecular Sequence Data; D010960:Plasminogen Activators / Q000378:metabolism*; D011817:Rabbits; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000577:Amides; D005343:Fibrinolytic Agents; D001120:Arginine; D010960:Plasminogen Activators; D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator