Plasminogen Activation in Diabetes Mellitus: Kinetics of Plasmin Formation with Plasminogen and Tissue Plasminogen Activator from Diabetic Donors

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Abstract
Impaired function of the fibrinolytic system might be involved in the development of vascular disease and thromboembolic complications in diabetic patients. We studied kinetics of plasmin formation using t-PA and Pg purified from the plasma of three individual uncontrolled type I diabetic patients. Activation of diabetic Pg by normal t-PA in the presence of stimulating CNBr fragments of fibrinogen exhibited a prolonged lag phase (30 to 60 minutes) until maximally stimulated plasmin formation occurred (normal, 5 to 15 minutes) and substrate inhibition at Pg concentrations more than 10 to 30 nM. When normal Pg was activated by diabetic t-PA in the presence of CNBr-f, differentiation between lag phase and phase of maximal plasmin formation was not possible (activation time was 2 hours) and a high Km (7.5 microM) was calculated. After normalization of metabolic parameters in the patients studied, functional properties of t-PA and Pg improved. Km of diabetic t-PA returned to normal values (0.02 to 0.09 microM) and for diabetic Pg the prolonged lag phase was shortened, indicating that the functional abnormalities were reversible and possibly caused by metabolically induced changes (such as nonenzymatic glucosylation) in the t-PA or plasminogen molecule. We also studied the effect of in vitro glucosylation on functional properties of Pg. Similar, but less pronounced substrate inhibition as with diabetic Pg was observed when this glucosylated Pg was activated by t-PA in a system stimulated by CNBr fragments of fibrinogen. Therefore nonenzymatic glucosylation might explain, at least in part, functional abnormalities observed with Pg from diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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