Experimental studies on thrombosis and thrombolysis : With special reference to importance of lys-plasminogen, active site thrombin inhibitors and stable fish oil

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Dissolution and prevention of thrombus in the atherosclerotic coronary artery have become an important part of treatment therapy of acute myocardial infarction. However, the currently most effective thrombolytic agent, recombinant tissue-type plasminogen activator (rt-PA), only elicits 80% recanalization of thrombotically occluded coronary arteries and early occlusion occurs in about 40% of successfullyrecanalized vessels.To achieve prompt and persistent thrombolysis, studies were constructed with glu- or lys-plasminogen, the substrate of rt-PA. Dogs with left anterior descending coronary artery (LAD) thrombus were treated with saline, glu-plasminogen or lys-plasminogen followed by infusion of rt-PA. Lys-plasminogen, but not glu-plasminogen, significantly accelerated the thrombolytic process induced by rt-PA and reduced the early reocclusion rate to 0%.Since increased thrombin activity has been associated with a delay in coronary thrombolysis or with early reocclusion, the effects of addition of the direct thrombin inhibitor inogatran were also examined. Inogatran at an optimal dose given with rt-PA totally prevented early reocclusion in the thrombotic coronary artery by inhibiting the generation and activity of thrombin. Aspirin given with suboptimal doses of inogatran did not potentiate the thrombolytic effect of rt-PA, or prevent coronary artery early reocclusion. To test whether an oral thrombin inhibitor will delay or prevent the formation of occlusive thrombus, anesthetized dogs were given saline or a single dose of a novel direct low molecular weight thrombin inhibitor melagatran by nasogastric tube before thrombus was induced. The study demonstrated that melagatran significantly delayed the formation of thrombus in the coronary artery through inhibition of thrombin, suggesting that long-term oral treatment with melagatran may be an attractive way to prevent arterial thrombosis.These observations imply that local depletion of plasminogen at the site of a thrombus is related to the limited thrombolytic efficacy and short-lasting effects of rt-PA. Generation of large amounts of thrombin is a critical factor in coronary artery thrombosis and early reocclusion after thrombolysis. We also examined the influence of dietary stable fish oil on FeCl3-induced aortic thrombosis in a rat model. The results indicated that dietary stable fish oil decreases the tendency to arterial thrombosis probably by reducing platelet aggregation and oxidative stress-associated arterial injury.

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