Increased tissue factor pathway inhibitor activity in IDDM patients with nephropathy

OBJECTIVE Tissue factor pathway inhibitor (TFPI) is bound to vascular endothelium (presumably to heparan sulfate) and circulates in complex with plasma lipoproteins. It directly binds and inhibits factor Xa. The purpose of the study is to investigate whether plasma TFPI activity is altered in IDDM and nephropathy and to evaluate the possible determinants of the alteration. RESEARCH DESIGN AND METHODS We assessed plasma concentration of TFPI (total, truncated, and domain 3 TFPI) and plasma activity of factor Xa inhibition in nondiabetic control subjects (n = 22) and in IDDM patients with normoalbuminuria (urinary albumin excretion rate [UAE] < 30 mg/24h, n = 17), incipient nephropathy (UAE 30-300 mg/24 h, n = 17), clinical nephropathy (UAE > 300 mg/24h, n = 25). RESULTS Total, truncated, and domain 3 TFPI concentrations were increased in IDDm patients compared with those in control subjects and were more pronounced in IDDM patients with nephropathy. Plasma activity of factor Xa inhibition measured by HEPTEST (Haemachem, St. Louis, MO) assay was increased in IDDM patients, especially in those with nephropathy. TFPI-dependent factor Xa inhibition, obtained as the difference in clotting time with and without adding activity-neutralizing anti-TFPI antibody to samples, was increased in IDDm patients with nephropathy. This was, however, not sufficient to inhibit the biological activity of factor Xa as demonstrated by increased levels of prothrombin fragment 1 + 2. LDL cholesterol and HbA1c were independently correlated to plasma TFPI. CONCLUSIONS Inhibition of factor Xa activity is increased in IDDM patients with nephropathy, mainly because of increased plasma TFPI activity. The increased plasma TFPI activity in these patients may be associated with and regulated by LDL in plasma and metabolic control. The anticoagulant activity of TFPI may attenuate the hypercoagulable state in diabetes but does not seem to be able to normalize hemostasis.