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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 736-741
Copyright © 2003 by The Endocrine Society

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

Yutaka Yano, Nagako Kitagawa, Esteban C. Gabazza, Kohei Morioka, Hideki Urakawa, Takashi Tanaka, Akira Katsuki, Rika Araki-Sasaki, Yasuko Hori, Kaname Nakatani, Osamu Taguchi, Yasuhiro Sumida and Yukihiko Adachi

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 2 DIABETIC PATIENTS showed enhanced activation of the blood coagulation system (1, 2, 3, 4, 5). This increased procoagulant activity is believed to be one of the factors that contributes to the high incidence of premature macro- and microangiopathy and increased morbidity and mortality, attributable to myocardial infarction, nephropathy, and retinopathy observed in diabetic patients (1, 2, 3, 4, 5). Thrombus formation results from disruption of the equilibrium between prethrombotic and antithrombotic factors that control clotting homeostasis; this imbalance may occur due to an ongoing stimulus to thrombogenesis, a defect of the natural anticoagulant or fibrinolytic system. Perturbance of homeostasis has also been implicated in the development of microvascular complications such as nephropathy and retinopathy in diabetic patients (3, 4, 5). However, the mechanism by which increased activation of the clotting system occurs in diabetic patients is not clear. Hypofibrinolysis, a common finding in diabetes may also be an important cause of vascular thrombosis; hypofibrinolysis alone is sufficient for extended fibrin deposition, even without preceding enhanced coagulation (6, 7). The clinical relevance of the fibrinolytic function in the pathogenesis of thrombosis in diabetes is illustrated by the positive correlation of hypofibrinolysis with the presence and severity of diabetic nephropathy (4).

In the present study, we focused our attention on the mechanism of hypofibrinolysis that occurs in type 2 diabetic patients with nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI) or carboxypeptidase U, has been isolated and characterized from human plasma (8). TAFI can be activated by thrombin-catalyzed proteolysis to a carboxypeptidase B-like enzyme that inhibits fibrinolysis. It was reported that plasma TAFI levels are likely to affect the activation rate of TAFI (9). There is no report regarding the relationship between plasma TAFI levels and diabetic nephropathy. The present study was undertaken to assess the circulating levels of TAFI in type 2 diabetic patients with nephropathy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

This study comprised 39 nonobese type 2 diabetic patients (27 men and 12 women) diagnosed according to the criteria of the American Diabetes Association (10). Data obtained in 20 age-matched, healthy volunteers (16 men and 4 women) with normal glucose tolerance were available for comparison. Informed consent was obtained from all patients before the beginning of the study. Subjects with clinical or laboratory signs of liver disease, malignancy, or a history of coagulation disorder were excluded from the study. Diabetic patients presented no history of ischemic heart disease, cerebral vascular accident, or intermittent claudication. None of the patients had arterial hypertension (<140/90 mm Hg), severe nephropathy (serum creatinine <= 100 µmol/liter), or orthostatic hypotension. None of the patients was receiving antihypertensive drugs before the beginning of the study. Twenty-four patients were being treated with diet therapy alone, 15 with oral hypoglycemic agents without thiazolidine. Albuminuria was measured in urine collected during 24 h, and repeated measurements (3 times) were performed to evaluate the mean value of urinary albumin excretion rate (UAE) after admission. According to the criteria of Mogensen and Christensen (11), 27 patients showed normoalbuminuria (<20 µg/min), and 12 patients showed microalbuminuria (20–200 µg/min). Fundi of the patients were examined by an ophthalmologist. The grade of retinopathy was determined by using a binocular indirect ophthalmoscope after applying a mydriatic agent (tropicamide). The findings were classified as follows: no change, with background, or with proliferative diabetic retinopathy. Five patients (1 with normoalbuminuria, 4 with microalbuminuria) had proliferative retinopathy, 7 (4 with normoalbuminuria, 3 with microalbuminuria) had background retinopathy, and 27 had normal findings. Patients were categorized as having symptomatic symmetrical diabetic neuropathy based on the presence of paresthesia or numbness, reduced or absent patellar tendon reflex, or reduced vibratory perception. On the basis of these criteria, diabetic peripheral neuropathy was found in eight patients (three with normoalbuminuria, five with microalbuminuria). Cardiovascular autonomic neuropathy was assessed by the coefficient of variation of R-R intervals during deep breathing (6 times/min) with 100 beats. No patient had abnormal values of coefficient of variation of R-R intervals, confirming that none of our patients had autonomic dysfunction.

Laboratory measurements

The glycosylated hemoglobin (HbA1c) levels (normal range, 4.3–5.8%) were measured by HPLC. Plasma glucose levels were measured by a glucose oxidase method. The serum levels of lipids were measured by automated enzymatic methods. Serum insulin levels were measured by using an immunoradiometric assay (Insulin Riabead II kit, Dinabot, Tokyo, Japan). Blood sampling was performed in all subjects from an antecubital vein after fasting overnight and resting over 30 min in the supine position after admission. Serum and plasma were separated by centrifuging at 1500 x g at 4 C for 20 min and then stored at -80 C until use. Urinary albumin concentration was measured at least three times in urine collected during 24 h by immunoturbidimetric assay using the EsupaMAB immunokit (Nipro, Osaka, Japan). The interassay and intra-assay coefficients of variability were less than 3%. Glomerular filtration rate (GFR) was estimated by creatinine clearance, calculated using urine collected for 24 h.

The plasma levels of thrombin-antithrombin complex (TAT) were measured by an enzyme immunoassay (EIA) using a 96-well plate coated with antihuman TAT monoclonal antibody and, as a second antibody, a biotin-labeled antihuman TAT monoclonal antibody (12). The interassay and intraassay coefficients of variability were less than 10%. The plasma levels of D-dimer (DD) were measured using commercial EIA kit (DD test-F, Kokusai Co., Kobe, Japan; Ref. 12). The plasma levels of soluble thrombomodulin were measured by EIA kit [human sCD141 (thrombomodulin) EIA kit, Diaclone Research, Besançon, France; Ref. 4). The interassay and intraassay coefficients of variability were less than 10%. The plasma levels of TAFI were also measured using a commercially available EIA kit (TAFI-EIA, Kordia Laboratory Supplies, Leiden, The Netherlands) (12). Briefly, sheep antihuman TAFI antibody, diluted in 0.1 M NaHCO3 buffer (pH 9.3), was coated on microtiter plates by overnight incubation. After washing with the same buffer, blocking of unspecified bindings was performed for 3 h at room temperature with PBS containing 1% BSA. Washing with EIA buffer [0.05 M Tris-HCl, 0.15 M NaCl (pH 7.5), 0.1% BSA, 0.01% Tween 20] was then carried out, and 100 µl horseradish peroxidase-conjugated sheep antihuman TAFI was added to each well and incubated for 1 h. After appropriate washing, peroxidase substrate was added to each well, and absorbance was measured at 450 nm. The interassay and intraassay coefficients of variability were less than 10%.

Statistical analysis

Data are expressed as the mean ± SEM. Statistical analyses were performed using the Stat View software package (Abacus Concepts, Berkeley, CA) for the Macintosh. The statistical difference among three groups was calculated by Kruskal-Wallis test, and the difference between the mean of two variables was calculated by Mann-Whitney U test. Univariate and multivariate analyses were performed to evaluate the relation of TAFI with markers of endothelial damage, glucose level, and renal function. A P value less than 0.05 was considered as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical profile of normal subjects and diabetic patients is described in Table 1Go. Diabetic patients with hypertension, hepatic, or renal dysfunction were excluded from the study. TAT, a marker of coagulation activation, was significantly increased in all diabetic patients compared with normal subjects (22.1 ± 2.6 vs. 8.3 ± 1.0 nmol/liter; P < 0.05). The ratio between the plasma levels of DD and TAT (DD/TAT) was calculated as an index of fibrinolytic activity; this DD/TAT ratio was significantly decreased in type 2 diabetic patients compared with normal subjects (15.7 ± 1.4 vs. 26.5 ± 2.2; P < 0.05; Fig. 1Go). These results suggest that hypercoagulability and hypofibrinolysis occur in type 2 diabetic patients. There was no significant difference in the plasma levels of fasting glucose, HbA1c, serum levels of fasting insulin and lipid profile between diabetic patients with normoalbuminuria and those with microalbuminuria (Table 1Go).


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  		Table 1. Characteristics of normal subjects and diabetic patients

 


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  		Figure 1. Plasma DD/TAT in normal subjects and type 2 diabetic patients. The plasma DD/TAT ratio was significantly decreased in diabetic patients (n = 39) compared with normal subjects (n = 20).

 
The plasma levels of TAFI were significantly higher (147.4 ± 11.6 vs. 99.5 ± 4.9%; P < 0.05) in all diabetic patients than in normal subjects. The plasma levels of TAFI were significantly increased in diabetic patients with microalbuminuria compared with those in diabetic patients with normoalbuminuria (194.1 ± 24.5 vs. 128.8 ± 12.3%; P < 0.02; Fig. 2Go) and in normal subjects (194.1 ± 24.5 vs. 99.5 ± 4.9%; P < 0.005; Fig. 2Go). The plasma levels of soluble thrombomodulin were significantly increased in diabetic patients with microalbuminuria compared with normal subjects (4.9 ± 0.5 vs. 3.1 ± 0.2 ng/ml; P < 0.01; Table 1Go). Univariate analysis showed that the plasma levels of TAFI are positively and significantly correlated with UAE (r = 0.58; P < 0.005; Fig. 3Go), with the plasma levels of soluble thrombomodulin (r = 0.42; P < 0.01; Table 2Go), and inversely and significantly correlated with GFR (r = -0.38; P < 0.05; Table 2Go). Multivariate analysis also showed that the plasma levels of TAFI are significantly correlated with UAE (P < 0.05; Table 2Go), but weakly with the plasma levels of thrombomodulin (P = 0.06; Table 2Go).



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  		Figure 2. Plasma TAFI levels in normal subjects and type 2 diabetic patients. The plasma TAFI levels were significantly increased in type 2 diabetic patients with microalbuminuria compared with those with normoalbuminuria and normal subjects. DM, Diabetes mellitus.

 


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  		Figure 3. Relationship between plasma TAFI levels and UAE. The plasma levels of TAFI were significantly correlated with UAE-Log in all diabetic patients.

 

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  		Table 2. Results of the univariate and multivariate analysis with TAFI as the dependent variable

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The fibrinolytic pathway is an important regulator of the coagulation cascade. A balance between the coagulation and fibrinolytic pathways is necessary for protection from excessive bleeding during injury, and at the same time to maintain blood fluidity within the vascular system. Alterations in the balance between fibrin deposition and its lysis may also cause hypercoagulability in diabetes (13). In accordance with this, we found increased plasma levels of the clotting activation marker TAT and decreased values of the fibrinolysis index DD/TAT ratio in diabetic patients compared with healthy subjects. These data confirmed the existence of hypercoagulability in diabetic patients (4). A pivotal event that controls the coagulation/fibrinolysis balance in vivo is the binding of thrombin to thrombomodulin on the vascular endothelial cell surface (14). The thrombomodulin-thrombin complex may promote coagulation by activating TAFI, which is a potent inhibitor of fibrinolysis (15). Activated TAFI inhibits fibrinolysis by removing C-terminal lysine residue, which are high-affinity binding sites for plasminogen (16). In the present study, the plasma concentration of TAFI was markedly increased in type 2 diabetic patients compared with healthy subjects. These results suggest the involvement of TAFI in the mechanism of hypofibrinolysis in diabetes.

An important finding in the present study is the significant increase of plasma TAFI levels in diabetic patients with microalbuminuria and its significant correlation with UAE. The mechanism of TAFI increase in diabetic patients with microalbuminuria is unclear. Microalbuminuria may result from both systemic vascular endothelial cell injury (17, 18, 19) and hyperglycemia-induced glomerular damage (20, 21). Besides liver cells, endothelial cells may also produce TAFI. Hyperglycemia and other metabolic abnormalities may injure vascular endothelial cells and stimulate them to secrete TAFI, and this may explain in part the increased plasma level of TAFI in patients of type 2 diabetes with microalbuminuria (17, 18, 19). Plasma thrombomodulin may also increase by cleavage and release of membrane-bound thrombomodulin from damaged vascular endothelial cells in diabetic patients (22, 23). The fact that plasma soluble thrombomodulin was significantly and proportionally correlated with TAFI by univariate analysis suggests that abnormal increase of TAFI may also be involved in the mechanism of systemic endothelial cell damage. Several fragments of thrombomodulin circulate in human plasma (24, 25). Short fragments of soluble thrombomodulin containing epidermal growth factor-like domain may activate TAFI (26, 27), and in diabetic patients, short fragments of soluble thrombomodulin have been reported to be elevated in plasma, suggesting that elevated plasma thrombomodulin may also be involved in increased activation of circulating TAFI.

The weak correlation between TAFI and thrombomodulin in the multivariate analysis suggests that, besides vascular endothelial injury, other factors including substances released by monocytes and platelets may be involved in the increased circulating level of TAFI in diabetic patients (28, 29, 30). For example, it was reported that expression of tissue factor, the initiator of blood coagulation activation, is increased in cultured monocytes stimulated with advanced glycosylation end products (31, 32). Moreover, tissue factor expression in monocyte is increased in diabetic patients with microvascular complications (33). Therefore, elevation of tissue factor in monocyte may also influence the circulating level of TAFI in diabetes. Activation of platelets with release of thromboxane A2 induced by oxidative stress has also been reported to activate the coagulation system, and thus it may also influence the level of TAFI in diabetic patients (30, 34, 35, 36). Thus, several factors or functional alteration of monocytes and platelets may affect the circulating levels of TAFI in diabetic patients.

In summary, the present study showed for the first time that circulating TAFI is significantly increased in diabetic patients with microalbuminuria, suggesting that TAFI is involved in the mechanism of endothelial cell injury in these patients.


   Acknowledgments
 
We are very grateful to Naomi Hashimoto for her secretarial assistance in the preparation of this manuscript.


   Footnotes
 
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; HbA1c, glycosylated hemoglobin; TAFI, thrombin-activatable fibrinolysis inhibitor; TAT, thrombin-antithrombin complex; UAE, urinary albumin excretion rate.

Received May 3, 2002.

Accepted October 24, 2002.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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