Enhanced thrombolysis by a factor XIIIa inhibitor in a rabbit model of femoral artery thrombosis.
Factor XIIIa (FXIIIa) catalyzes covalent crosslinking reactions of fibrin, affording the clot additional structural stability and resistance to plasmin-mediated degradation. Thus, inhibition of FXIIIa may render thrombi more susceptible to tissue-plasminogen activator (t-PA)-induced thrombolysis in vivo. We therefore examined thrombus weight and time to lysis in anesthetized rabbits undergoing arterial thrombosis produced by insertion of a copper coil into the lumen of the right femoral artery. The effects of t-PA alone (started 30 min after coil insertion) or in combination with a FXIIIa inhibitor (L722151) started 15 min before, 8 min after or 20 min after coil insertion were determined. Although t-PA alone (2 mg/kg over 2 hrs) lowered thrombus weight significantly, there was no evidence of flow restoration. Addition of L722151 to t-PA before, or 8 min after coil insertion, further lowered thrombus weights and produced thrombolysis in 50% of the animals. This beneficial effect was lost when L722151 administration was delayed until 20 min after thrombus formation, suggesting that the type(s) of crosslinking inhibited by L722151 was complete by this time. Infusion of L722151 alone had no significant effect on thrombus weight. These results demonstrate a time-dependent facilitation of t-PA-induced arterial thrombolysis by FXIIIa inhibition in a small animal model.
Leidy
E M
EM
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Stern
A M
AM
Friedman
P A
PA
Bush
L R
LR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005263:Femoral Artery; D008297:Male; D011817:Rabbits; D013830:Thiadiazoles / Q000627:therapeutic use*; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D013830:Thiadiazoles; C063511:L 722151; D011503:Transglutaminases; D010959:Tissue Plasminogen Activator