Elevation of Plasma Thrombomodulin Level in Diabetic Patients With Early Diabetic Nephropathy

Abstract

Thrombomodulin (TM) is a membrane protein in the vascular endothelium, and it plays an important role as a cofactor in the thrombin-catalyzed activation of protein C. It has also been found in human plasma; however, its clinical significance is not known. In this study, fasting plasma TM concentrations in 67 diabetic patients with different degrees of albuminuria (39 men aged 57 ± 8 yr, 28 women aged 57 ± 11 yr; means ± SD) and 34 age- and sex-matched healthy subjects were investigated by use of a one-step sandwich enzyme immunoassay, a new method developed by H.I. and others. As a screening, the patients were divided into three groups according to the first morning urinary concentrations of albumin: group 1, <30 μg/ml (normoalbuminuria); group 2, 30–140 μg/ml (microalbuminuria); group 3, >140 μg/ml (clinical nephropathy). There was no significant difference in plasma TM level between the control group (17.7 ± 3.7 ng/ml, n = 34) and group 1 (16.9 ± 3.4 ng/ml, ± = 30); however, plasma TM concentrations in group 2 (22.8 ± 3.4 ng/ml, n = 22) and group 3 (29.6 ± 6.1 ng/ml, n = 15) increased significantly compared with those in the control group and group 1, respectively. As a further investigation, three timed overnight urine collections were made. The patients were allocated to three groups according to their rates of albumin excretion: group I, <20 μg/min (normoalbuminuria); group II, 20–200 μg/min (microalbuminuria); group III >200 μg/min (clinical nephropathy). No significant difference was found in plasma TM level between the control group (17.8 ± 3.8 ng/ml, n = 16) and group I (17.8 ± 3.0 ng/ml, n = 17); however, plasma concentrations in group II (22.1 ± 2.8 ng/ml, n = 18) and group III (29.2 ± 6.0 ng/ml, n = 13) increased significantly compared with those in the control group and group I, respectively. No significant differences were found in blood pressure between the control group, group I, and group II. The vascular endothelium could be injured by various metabolic derangements because of diabetes. Accordingly, it is supposed that an injury in the vascular endothelial cell may progress with the advance of diabetic angiopathy, and TM existing on the endothelial membrane surface may be released into the plasma. The vascular permeability that permits glomerular leakage of albumin may also be found in other vessels. Thus, our findings suggest that an increased influx of TM to the plasma may be caused by generalized endothelial damage in patients with early diabetic nephropathy.