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Increased Plasma Thrombin-Activatable Fibrinolysis Inhibitor Levels in Normotensive Type 2 Diabetic Patients with Microalbuminuria

Third Department of Internal Medicine (Y.Y., N.K., E.C.G., K.M., H.U., T.T., A.K., R.A.-S., Y.H., O.T., Y.S., Y.A.) and Department of Laboratory Medicine (K.N.), Mie University School of Medicine, Tsu, Mie 514-8507, Japan

Address all correspondence and requests for reprints to: Dr. Yutaka Yano, Third Department of Internal Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan. E-mail: yanoyuta{at}clin.medic.mie-u.ac.jp.

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 ± 2.6 vs. 8.3 ± 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 ± 1.4 vs. 26.5 ± 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 ± 11.6 vs. 99.5 ± 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 ± 24.5 vs. 128.8 ± 12.3%; P < 0.02) or normal subjects (194.1 ± 24.5 vs. 99.5 ± 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.

Y.Y. and N.K. contributed similarly to the completion of this work.

This work was supported by a Grant in Aid (2001) from the Mie Medical Research Foundation.

Abbreviations: DD, D-Dimer; EIA, enzyme immunoassay; GFR, glomerular filtration rate; HbA_1c, glycosylated hemoglobin; TAFI, thrombin-activatable fibrinolysis inhibitor; TAT, thrombin-antithrombin complex; UAE, urinary albumin excretion rate.

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