Local regulation of the endogenous fibrinolytic system in man

Abstract: The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (tPA). The endothelium synthesises and stores tPA and regulated release of the enzyme is an important mechanism for removal of fibrin from blood vessels. Plasminogen activator inhibitor type-1 (PAI-1) is the main inhibitor of tPA. The aim of the present thesis was to study how the local availability of free tPA is regulated under baseline conditions and during stimulated tPA release, to explore the potential role of extracellular nucleotides as potential mediators of tPA release in tissue injury and ischaemia, and to analyse if the capacity for tPA is decreased in hypertension and advanced chronic renal failure, and if so which mechanism may be involved.The studies were performed in 115 healthy subjects, seven patients with essential hypertension, and nine patients with advanced chronic renal failure. The release of tPA and PAI-1 was studied in a perfused-forearm model, at baseline and during stimulation with sodium nitroprusside, methacholine, desmopressin, or the extracellular nucleotides ATP and UTP. Also, the synthesis and secretion of tPA were studied in human conduit vessels perfused with high versus low intraluminal pressure ex vivo. During the morning hours the fibrinolytic activity increased secondary to an increase in the endothelial release of tPA and a decrease in the overall availability of its inhibitor PAI-1. The capacity for stimulated tPA release was not predicted from either plasma concentrations of the activator or its inhibitor, or from the basal release rate of these proteins. The local availability of free active tPA during stimulation of tPA release was dependent on the tPA release rate and not the inflow/release of inhibitors (PAI-1). The extracellular nucleotides ATP and UTP were found to induce regulated tPA release, which in the case of UTP was independent of NO and prostaglandin synthesis. Nucleotide stimulated tPA release may be a potential mechanism for activation of the thromboprotective programme.The capacity for regulated tPA release was found to be markedly impaired in patients with hypertension and advanced chronic renal failure. A potential mechanism is that high blood pressure in it self impairs regulated tPA release, as high intraluminal perfusions pressure inhibited tPA synthesis and release in endothelial cells ex vivo.In conclusion, these findings support the hypothesis that regulated tPA release is the major determinant of the local availability of active tPA. It was therefore of interest to find the capacity for stimulated tPA release to be reduced in patients with hypertension and advanced chronic renal failure, an impairment that potentially increases the susceptibility for atherothrombosis.