Increased tissue-type plasminogen activator: a facade in the fibrinolytic system in type 2 diabetes

Abstract

To determine whether the increased concentration in blood of total tissue-type plasminogen activator (t-PA), accompanying increased plasminogen activator inhibitor type-1 (PAI-1) seen with diabetes reflects increased free t-PA and hence activity or simply increased t-PA complexed with PAI-1, we measured each in 39 people with type 2 diabetes. The increased total t-PA occurred in the absence of an increase in t-PA activity detectable in venous blood samples despite the increase in the concentration of total t-PA protein. Type 2 diabetes is known to be associated with increased concentrations in blood of total tissue-type plasminogen activator (t-PA) [free t-PA plus t-PA complexed with plasminogen activator inhibitor type-1 (PAI-1)] and PAI-1. This study was performed to determine whether the increased total t-PA is indicative of increased t-PA activity attributable to free t-PA or whether it is simply a manifestation of compensatory processes maintaining t-PA activity detectable in venous blood samples at normal or subnormal levels. Total t-PA, free t-PA, and PAI-1 antigen and activity were measured by enzyme-linked immunosorbent assay and immunofunctional chromogenic substrate kinetic assays in peripheral venous blood samples obtained under fasting conditions from 39 people with type 2 diabetes. The results indicate that both PAI-1 and total t-PA antigen concentrations were increased in association with diabetes but the concentration of free t-PA and hence the t-PA activity was not. Thus, the increased total t-PA is a facade potentially masking the impaired fibrinolytic system activity associated with type 2 diabetes. The results indicate that the increase in the concentration of total t-PA protein in blood of people with diabetes occurs in the absence of an increase in free t-PA. Hence t-PA activity detectable in peripheral venous blood samples does not increase and may even decline modestly.