Mechanisms of thrombosis and restenosis after vascular injury

Abstract: Atherosclerosis is the underlying cause of about 50% of all deaths in the western world. Peripheral vascular disease commonly affects the arteries supplying the leg and is mostly caused by atherosclerosis. When medical treatment of lower extremity ischemia has failed, percutaneous transluminal angioplasty (PTA) and bypass surgery are two major therapeutic options. The advances in vascular surgery and endovascular techniques over the past half-century have greatly expanded the number of arterial lesions that can be treated. The major limitations of a successful revascularisation are thrombosis and the later development of restenosis. This thesis has explored the mechanisms of thrombosis and restenosis after vascular injury, focusing on the interaction between coagulation, inflammation, and oxidative stress. The long-term outcome of infrainguinal PTA was evaluated in 77 patients. Cumulative primary and secondary patency rates, respectively, were 81% and 86% at 1 year, 65% and 73% at 5 years, and 12% and 17% at 10 years. Patency rates were better for patients with claudication than critical ischemia. Stenoses had better primary patency than occlusions. Generalised femoral artery disease and diabetes mellitus predicted poor survival. Although the overall long-term patency of infrainguinal PTA is poor, the technique has a low morbidity and can be performed in selected patients with a reasonable long-term result. If conservative treatment has failed infrainguinal PTA should be considered, when lesions and patients are suitable, because of its minimal invasive nature. It is also important when treating patients with peripheral arterial disease to give attention to their general cardiovascular condition. In an experimental study a specific direct thrombin inhibitor, inogatran, reduced neointimal hyperplasia after arterial injury in rats. A more prolonged administration of the thrombin inhibitor gave a further reduction of the neointimal hyperplasia. It seems that inhibition of thrombin activity is not only important early after injury, but also later. This could have clinical implications in the treatment of restenosis. Inflammation and oxidative stress in the vessel wall may play important roles in the development of restenosis after angioplasty. In patients with peripheral arterial disease, a much more prolonged inflammatory response than previously noted was observed after angioplasty, but only minor changes in coagulation activity. C-reactive protein was elevated the day after angioplasty and peaked after one week. Coagulation and inflammatory markers were not significantly related to restenosis. The redox-active protein, thioredoxin, was significantly elevated 4 hours after angioplasty and returned to baseline within 24 hours. Circulating thioredoxin could theoretically impair the chemotactic response at local sites of inflammation. An association in patients with elevated levels of thioredoxin after angioplasty and reduced restenosis needs to be further evaluated. This thesis has discussed the intimate relation between thrombosis, inflammation, oxidative stress, and restenosis. Further studies are needed to delineate the molecular mechanisms behind these observations and their involvement in thrombosis and restenosis. It is not only important to be able to understand the individual pathways of these processes, but also the ways they intersect and interact. If these pathways are further defined, improved treatment strategies, including antithrombotic treatments, statins, and thioredoxin, to modulate postprocedure inflammation could be tailored.