Until now, several endothelium-dependent hemostatic parameters have been proposed as markers of vascular endothelial dysfunction in diabetes. We studied tissue factor pathway inhibitor (TFPI) activity in insulin-dependent diabetes mellitus (IDDM) patients without macro-or microvascular complications, before and after intravenous administration of heparin, in comparison with age-matched control subjects. We also examined the effect of acute hyperglycemia on TFPI activity in healthy men. A clotting and a chromogenic assay were used for determining TFPI activity. In the clotting assay, the COOH-terminus of TFPI is essential, but in the chromogenic assay, it is of minor importance. When the chromogenic assay was used, TFPI activity before heparin injection was significantly higher in the IDDM patients (92 ± 24 vs. 112 ± 23%, P < 0.01). The postheparin increase in TFPI activity, measured with both assays, was significantly higher in the diabetic subjects (area under the curve: clotting assay 64 ± 14 vs. 81 ± 24, P < 0.05; chromogenic assay 82 ± 26 vs. 121 ± 35, P < 0.0001). A positive correlation between TFPI activity and glycated hemoglobin was demonstrated. Acute hyperglycemia did not alter TFPI activity. It can be concluded that TFPI activity, especially after stimulation with heparin, is affected by chronic hyperglycemia in diabetic subjects without vascular complications. Alterations in TFPI activity may therefore reflect early endothelial dysfunction.

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