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We studied the relationships between albuminuria, tissue factor-induced coagulation, and endothelial cell dysfunction in 67 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were divided into three groups on the basis of their urinary albumin excretion rate (AER). To assess the early phase of tissue factor-induced coagulation, activated factor VII (FVIIa) levels in plasma were measured by a direct fluorogenic assay. As markers of endothelial cell dysfunction, levels of von Willebrand factor (vWF), tissue-type plasminogen activator-plasminogen activator inhibitor-1 (TPA-PAI-1) complex, PAI-1, and tissue factor pathway inhibitor (TFPI) were measured. FVIIa levels were increased in normoalbuminuric NIDDM patients (AER < 15 micrograms/min) when compared with normal control subjects. This FVIIa increase was accompanied by an increase in thrombin-antithrombin III complex (TAT) levels, indicating increased activation of coagulation even in normoalbuminuric patients. In NIDDM patients with microalbuminuria (AER = 15-200 micrograms/min), the FVIIa level, the FVIIa-FVII antigen (Ag) ratio (an indicator of activation of FVII zymogen to FVIIa), and the TAT level were further increased. This group also had higher levels of endothelial cell-derived factors (vWF, TPA-PAI-1 complex, and PAI-1) than the control group. The levels of endothelial cell-derived factors (including TFPI) were highest in the NIDDM patients with overt albuminuria (AER > 200 micrograms/min). In all 67 diabetic patients, AER showed a strong positive correlation with FVIIa (r = .574, P < .0001) and a weakly but still significant correlation with FVIIa-FVII:Ag (r = .365, P = .01), vWF (r = .315, P < .01), and TAT (r = .323, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Factor VII (FVII) plays an important role in initiation of the tissue factor-induced coagulation pathway. An increase in FVII coagulant activity (FVIIc) has been proposed as an independent risk factor for coronary artery disease. However, it remains uncertain whether high FVIIc levels are due to an increase in the activation of FVII or an increase in the concentration of FVII mass. We developed a new fluorogenic assay for plasma activated FVII (FVIIa) that used soluble tissue factor. The sensitivity of this assay ranged from 0.2 to 1000 ng FVIIa per milliliter of plasma. Plasma FVIIa levels were measured in 110 healthy subjects and 93 patients with hypertension, diabetes mellitus, and/or cardiovascular disease. The mean plasma FVIIa level in healthy Japanese individuals was 2.5 ng/mL, which was lower than that in Western subjects. Gel filtration analysis showed that most of the circulating FVIIa was in a free form, and binding of FVIIa to tissue factor in plasma was not detected. Aging increased both the FVIIa level and FVII mass, whereas menopause increased mainly the FVII mass. Elderly patients with arterial cardiovascular diseases showed increases in plasma FVIIa levels and FVIIa to FVII antigen (FVII:Ag) ratios. Among the elderly, arterial cardiovascular disease was more common in a high-FVIIa than a low-FVIIa group. Plasma FVIIa levels were not correlated with serum levels of total cholesterol or triglycerides. The FVIIa level and the FVIIa-to-FVII: Ag ratio were positively correlated with fibrinogen level and negatively correlated with body mass index and serum albumin level in the elderly. In conclusion, aging, cardiovascular disease, and malnutrition increased plasma FVIIa levels. FVIIa levels were not correlated with lipid levels or hepatic synthesis, suggesting that FVIIa may be an independent risk factor for cardiovascular disease. (Arterioscler Thromb. 1994;14:265-274.)