Inhibition of Heparin-Catalyzed Human Antithrombin III Activity by Nonenzymatic Glycosylation: Possible Role in Fibrin Deposition in Diabetes

Abstract

The effect of nonenzymatic glycosylation on the biologic function of human antithrombin III was evaluated using a chromogenie thrombin substrate assay in the presence of catalytic amounts of heparin. Experimental conditions that increased the rate of nonenzymatic protein glycosylation were associated with decreases in the thrombin-inhibiting activity of antithrombin III. This glycosylation-induced inhibition of heparin-catalyzed antithrombin III activity was completely reversible by preassay incubation with excess sodium heparin. These observations provide a biochemical explanation for the heparin-reversible, accelerated fibrinogen disappearance rate induced by hyperglycemia in diabetic patients. Defective inhibition of the coagulation cascade induced by excessive nonenzymatic glycosylation of antithrombin III in vivo could contribute to accumulation of fibrin in various diabetic tissues.