Belcher, Philip Rashleigh; (1993) Aspects of intracoronary thrombosis. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Since the discovery of platelet-rich thrombus, within the coronary arteries of people dying suddenly, attempts have been made to modify platelet behaviour. Aspirin may be only partially effective, is often poorly tolerated, and increases bleeding time. Non-specific thrombin inhibition by heparin is widely practised; this has some benefits but prolongs clotting and bleeding times. Using a canine model of critical coronary stenosis and endothelial damage, a number of anti-platelet agents were studied. The specific thrombin inhibitor r-Hirudin caused increases in bleeding, thrombin and partial thromboplastin times but was relatively inneffective in preventing intracoronary platelet thrombosis. Trimetazidine is a drug which may prevent intracellular calcium entry. This abolished or reduced thrombosis without affecting bleeding or coagulation. The next target was the platelet serotonin 5HT₂ receptor. Experiments with the selective 5HT₂ antagonists MDL 11.939 and LY 53,857 completely abolished intracoronary platelet thrombosis without evidence of coagulopathy. The pattern of flow restoration suggested thrombolytic activity. Further studies of the use of these drugs (and ICI 170,809, another selective 5HT₂ antagonist) in combination with the thrombolytic agent rt-PA confirmed the effectiveness of these agents. There were no adverse effects on coagulation or bleeding times. During experiments in which intracoronary pressure was measured, it was noted that, despite a severe proximal stenosis, post-stenotic coronary resistance changed in response to increase in flow; these changes were accentuated by the presence of platelet thrombosis. The selective 5HT₂ antagonists, some of which have undergone unsuccessful trials for the treatment of migraine, anxiety and depression, show the greatest promise for the treatment of acute coronary syndromes in humans. The effectiveness of these compounds, and trimetazidine, which do not adversely affect coagulation, suggests that the two processes are not inextricably linked.

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