Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion.
The objectives of this study were to test the hypotheses that thrombin inhibitors 1) enhance tissue-type plasminogen activator (t-PA)-induced coronary thrombolysis and 2) prevent or delay coronary artery reocclusion. Seventy-one dogs developed occlusive coronary thrombi after introducing a copper coil into the left anterior descending coronary artery (LAD). Coronary blood flows were monitored by an externally positioned pulsed Doppler flow probe. t-PA was given with or without heparin at different times after LAD occlusions. In some experiments, hirugen, a synthetic hirudin-based peptide and specific thrombin inhibitor, was given as 4 mg/kg i.v. bolus and 3 mg.kg-1.h-1 i.v. infusion at 30 min after LAD occlusion with t-PA and a bolus of heparin. Thrombolysis times were significantly shorter in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Reocclusion times were significantly longer in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Continuous heparin infusions prolonged reocclusion times to greater than 180 min in all treated dogs. The addition of hirugen to t-PA plus one bolus heparin prolonged reocclusion times to 90 +/- 6 min in dogs with 30-min thrombi. Thus heparin enhances t-PA-induced thrombolysis and delays reocclusion. Addition of a specific thrombin inhibitor, such as hirugen, to heparin enhances its effect on delaying reocclusion.
Yao
S K
SK
Department of Internal Medicine, University of Texas Medical School, Houston 77225.
McNatt
J
J
Anderson
H V
HV
Eidt
J
J
Cui
K X
KX
Golino
P
P
Glas-Greenwalt
P
P
Maraganore
J
J
Buja
L M
LM
Willerson
J T
JT
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003327:Coronary Disease / Q000517:prevention & control*; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation; D012008:Recurrence; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D006629:Hirudins; D010446:Peptide Fragments; C062510:hirugen; D006493:Heparin; D013917:Thrombin; D010959:Tissue Plasminogen Activator