Effect of aspirin and epinephrine on experimentally induced thrombogenesis in dogs. A parallelism between in vivo and ex vivo thrombosis models.
Thrombosis on the damaged or ruptured vascular wall in a stenotic coronary artery is believed to be the precipitating factor leading to unstable angina. Little is known about the nature of the interactions among platelets, fluid dynamic factors, and vessel wall properties under such conditions. In the present investigation we have compared two experimental models of thrombosis simultaneously in anesthetized dogs. The first was an in vivo model of unstable angina, in which a fixed circumflex coronary artery stenosis was produced and the resultant cyclic blood flow reductions (CFRs) through the vessel were investigated after infusion of aspirin and a combination of aspirin and epinephrine. As previously reported, aspirin inhibited the CFRs, but the continuous infusion of epinephrine reestablished the appearance of CFRs. The second was an ex vivo model, in which thrombus formation on a type III collagen surface was investigated in a parallel-plate perfusion system under controlled conditions of exposure time and flow; morphological evaluation of thrombus volume, platelet adhesion, and fibrin deposition was performed. The chamber was positioned in an extracorporeal shunt between the carotid artery and the jugular vein of anesthetized dogs and exposed to nonanticoagulated blood at a shear rate of 1,600 sec-1. Thirty minutes after establishment of the CFRs, a blood sample for platelet aggregation was collected and a bleeding time and a first ex vivo perfusion were performed. At the end of this perfusion, animals were subjected either to no treatment (n = 10) or to an intravenous bolus of 10 mg/kg aspirin (n = 7), and a second perfusion was conducted 30 minutes later. Additional untreated animals (n = 6) were given aspirin followed by a continuous intravenous infusion of 10 micrograms/ml epinephrine, and a third perfusion was conducted. Results with respect to platelet adhesion, thrombus volume, and fibrin deposition were similar in the two perfusions in untreated animals. Treatment with aspirin abolished the CFRs in all dogs and concomitantly reduced the ex vivo thrombus volume by 84% (p less than 0.01) without affecting platelet adhesion and fibrin deposition. Bleeding time increased by 40% (p less than 0.05), and collagen-induced platelet aggregation was virtually abolished (p less than 0.01). However, infusion of epinephrine in dogs after aspirin treatment restored the CFRs, and the ex vivo thrombus volumes were not statistically different from predrug values. Thus, the ex vivo model satisfactorily reflects the more complicated in vivo model events with respect to intracoronary thrombosis and substantiates the view that aspirin interrupts coronary thrombogenesis in the dog by interfering with platelet cohesion.
Roux
S P
SP
Pharma Division, Preclinical Research/PRPV, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Sakariassen
K S
KS
Turitto
V T
VT
Baumgartner
H R
HR
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001696:Biomechanical Phenomena; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects
D001241:Aspirin; D004837:Epinephrine