Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin.
BACKGROUND
The presence of residual mural thrombus may predispose to recurrent thrombotic events in acute coronary syndromes. The purpose of this study was to evaluate the effects of antithrombotic and antiplatelet agents on a preformed, fresh mural thrombus during growth of thrombus.


RESULTS
A fresh mural thrombus was formed by perfusing severely injured arterial wall with porcine blood for 5 minutes at a shear rate of 1690 s(-1). Thrombus formation was measured by morphometric analysis (mm2/mm). The average size of a mural thrombus formed in 5 minutes was 0.14+/-0.03 mm2/mm. Progression of thrombus growth within 10 minutes triggered by the preformed thrombus was evaluated in pigs treated with r-hirudin (1 mg/kg per hour i.v.) as a probe for thrombin, high-dose heparin (250 IU/kg per hour i.v.), moderate-dose heparin (100 IU/kg per hour), moderate-dose heparin (100 IU/kg per hour) plus aspirin, aspirin alone (5 mg/kg i.v.), and placebo. Hirudin was associated with a significant decrease (48%) of mural thrombus area and significantly reduced growth of thrombus (0.07+/-0.01), even compared with the highest dose of heparin (0.15+/-0.03), although at lower levels of anticoagulation. Inhibition of growth of thrombus with heparin was dose dependent, showing an inverse correlation of thrombus area with mean plasma heparin concentrations (r=.77, P=.0001). Thrombus size was unchanged by aspirin (0.29+/-0.07) compared with controls (0.28+/-0.07).


CONCLUSIONS
Direct inhibition of thrombin activity with r-hirudin completely inhibits growth of thrombus, causes dissolution of a preexisting mural thrombus, and is more effective at lower levels of anticoagulation than the highest dose of heparin at shear rates typical of a moderate coronary stenosis.
Meyer
B J
BJ
Department of Medicine, University Hospital Inselspital, Bern, Switzerland. bmeyer@insel.unibe.ch
Badimon
J J
JJ
Chesebro
J H
JH
Fallon
J T
JT
Fuster
V
V
Badimon
L
L
D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006331:Heart Diseases / Q000188:drug therapy*; D006400:Hematocrit; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy*
D005343:Fibrinolytic Agents; D006629:Hirudins; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D006493:Heparin; D013917:Thrombin; D001241:Aspirin; C060225:desirudin