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Some patients with von Willebrand's disease do not respond to stimuli such as venous occlusion and infusion of a vasopressin analogue DDAVP. In these patients, fibrinolytic activity is not enhanced and von Willebrand's factor is not released into the blood. Skin biopsies and cryostat sections were used to study the fibrinolytic activity of skin vessels and localization of tissue plasminogen activator (t-PA) in three patients with severe form of von Willebrand's disease. On fibrin films, no fibrinolysis developed around the skin vessels of the patients; however, using specific polyclonal and monoclonal antibodies to t-PA, and peroxidase coupled specific IgG, presence of t-PA antigen was demonstrated in endothelial cells (EC) of all of them. In plasma no t-PA activity was detected either before or after venous occlusion although t-PA inhibitor activity was in a normal range. Small amounts of t-PA antigen was measured in blood by ELISA. From these results, it is concluded that in patients with severe forms of von Willebrand's disease, t-PA present in EC is not functional and can not transform plasminogen into plasmin.