A MODEL OF ACUTE PLATELET THROMBUS FORMATION IN STENOSED CORONARY AND CAROTID ARTERIES
Authors: Folts J D 
Published: August 2018

There is currently a great deal of interest in the diagnosis and treatment of unstable angina and silent ischemia.Many feel that these syndromes are due, in part, to periodic accumulation of platelet thrombi which subsequently embolize.In addition, anti-piatelet therapy is also considered necessary for patients after coronary artery bypass grafts (CABG'S), balloon angioplasty, and thrombolysis. Currently the two antiplatelet agents most commonly prescribed for the patient conditions mentioned above are aspirin (ASA), alone or in combination with dipyridamole (Dip). ASA reduces cardiac events in patients with unstable angina, and prolongs CABG graft patency. The addition of Dip to ASA therapy is very confusing since most studies done compared ASA + Dip to placebo. In several studies however,when an ASA group was compared to an ASA + Dip group there was no significant difference.

We have developed and will describe ananimal model of coronary artery stenosis in the dog and the pig, or carotid arterystenosis in the monkey and the rabbit, with intimal damage, that simulates some ofthe conditions that exist in patients with coronary or carotid artery disease. The artery to be studied is dissected outand blood flow is continuously measured with an electromagnetic flowmeter probe. As acute platelet thrombus formation (APTF) developes in the stenosed lumen, the blood flow declines to low levels, producing ischemia until the thrombus emobolizesdistally resulting in abrupt restoration of blood flow. These cyclical flow reductions (CFR's), when they occur in the coronaries, produce ECG changes identical to those observed in patients with silent ischemia and unstable angina. They also produce significant transient regional dyskinesis of the ventricular wall, which resolves when blood flow is restored. Histologic examination of myocardial tissue in the bed distal to the stenosis shows focal areas of ischemic change presumably caused by the embolized platelet emboli.

We have examined factors which exacerbate the size and frequency of these CFR"ssuch as; IV infusion of epinephrine (E) 0.4 μg/kg/min for 15 min, ventilating the animals with cigarette smoke, infusing nicotine IV, or placing chewing tobacco under the tongue.

We have examined four groups of agentswhich prevent APTF in our model.1. Antiplatelet agents including ASA, indomethacin, ibuprofen and several other NSAI agentsas well as several experimental thromboxane synthetase inhibitors. These agents all block the production of TXA2and inhibit APTF in our model. Unfortunately the IV infusion of E reinstates APTtemporarily (by another biochemical pathway) until the E is metabolized. High (2-4 mg/kg) doses of Dip, alone or with sub threshold dose of ASA does nothing to I APTF.However,0.6mg/kg of chi orpromaz i ne abolishes APTF in all four species and protects agents renewal of APTF by E.

2. Dietary Substances In our model, caffeine 10 mg/kg, or the extract from two garlic cloves, or enough ethanol to achieve a blood alcohol level of 0.07 mg% all significantly inhibit or abolish APTF in our model.

3. Metabolic Inhibitors POCA, an oral hypoglycemic agent, which inhibits mitochondrial beta oxidation of fatty acids also inhibits APTF in our model possibly by reducing ATP production in the platelet.

4. We have studied a monoclonal antibody(developed by Dr. Barry Coller) to the platelet I Ib�I I la glycoprotein receptor where fibrinogen binds platelets into aggregates and ultimately leads to APTF. This antibody 0.3 mg/kg/completely inhibits APTF, and also strongly inhibits in vitro platelet aggregation in response to either ADP or collagen given alone or each combined with E. This antibody is the most potent inhibitor of APTF that we have studied.