Inhibition of platelet deposition by combined hirulog and aspirin in a rat carotid endarterectomy model.
OBJECTIVE
Hirulog, a thrombin-specific inhibitor, has shown efficacy in reducing arterial thrombosis in patients treated with aspirin who require angioplasty or have unstable angina. In this study, the effect of hirulog on reducing deposition of indium 111-labeled platelets was assessed in a surgical model of aspirin-treated rats undergoing carotid endarterectomy.


METHODS
Animals were randomly assigned to one of five groups: control (no aspirin or hirulog); aspirin alone (10 mg/kg); aspirin plus low-dose hirulog (0.2 mg/kg bolus followed by 0.5 mg/kg/hr); aspirin plus medium-dose hirulog (0.4 mg/kg bolus followed by 1.0 mg/kg/hr); or aspirin plus high-dose hirulog (0.6 mg/kg bolus followed by 1.5 mg/kg/hr). Hirulog was infused before surgery and continued until termination of the experiment 30 minutes after endarterectomy.


RESULTS
Platelet deposition in rats receiving aspirin alone was reduced by 19% +/- 23% SE (p = 0.26) compared with controls. Deposition in aspirin-treated groups receiving low-, medium-, and high-dose hirulog decreased in a dose-dependent manner by 37% +/- 20% (p = 0.048), 44% +/- 19% (p = 0.061), and 56% +/- 13% (p = 0.022), respectively. As the dose of hirulog was increased, the plasma hirulog levels and activated partial thromboplastin time ratios (final:initial) also increased in a dose-dependent manner. The mean plasma hirulog levels ranged from 0.74 +/- 0.08 micrograms/ml in the low-dose hirulog group to 2.55 +/- 0.08 micrograms/ml in the high-dose hirulog group, and the corresponding activated partial thromboplastin time ratios were 1.5 +/- 0.12 (p = 0.001) and 3.3 +/- 0.63 (p = 0.001). Bleeding was easily controlled by local hemostatic measures for all experimental groups.


CONCLUSIONS
Hirulog causes significant decrease in 111In-labeled platelet deposition in aspirin-treated rats subjected to microsurgical endarterectomy at doses that allow surgical hemostasis to be easily established.
Hamelink
J K
JK
Department of Hematology and Vascular Biology, Walter Reed Army Institute of Research, Washington, D.C.
Tang
D B
DB
Barr
C F
CF
Jackson
M R
MR
Reid
T J
TJ
Gomez
E R
ER
Alving
B M
BM
D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D016894:Endarterectomy, Carotid; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*
D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013917:Thrombin; D001241:Aspirin; C074619:bivalirudin