Tissue factor pathway inhibitor (TFPI) release after heparin stimulation is increased in Type 1 diabetic patients with albuminuria.

AIMS: To study heparin-stimulated TFPI release in relation to complications in Type 1 diabetic patients. SUBJECTS AND METHODS: Nineteen uncomplicated Type 1 diabetic patients (group I) were compared with 18 patients with retinopathy (group II), and nine patients with retinopathy and albuminuria (group III). Blood samples were taken before (basal) and till 30 min after 5000 IU of heparin i.v. (post-heparin). TFPI activity was measured chromogenically. Von Willebrand factor, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin were also measured. RESULTS: Basal TFPI activity was higher in group III (121 +/- 10%) compared with group II (111 +/- 8%) or group I (110 +/- 13%) (P < 0.05), and strongly correlated with albuminuria (r = 0.66, P < 0.05). At all time points after heparin administration, TFPI activity in group III was significantly higher than in group I. TFPI activity was also higher in group III than in group II 5-30 min post-heparin. The increase in post-heparin TFPI activity, measured as the incremental area under the curve, was higher in group III compared with group I (65 +/- 7 vs. 59 +/- 4; P < 0.05). Of the other parameters, only thrombomodulin was higher in group III (44 +/- 24 vs. 26 +/- 7 (group II) and 28 +/- 9 ng/ml (group I); P < 0.01). CONCLUSIONS: We conclude that basal and post-heparin TFPI activity is increased in albuminuric patients. The increase in heparin-stimulated TFPI release in patients with albuminuria is higher than in patients with retinopathy or without complications. This could be the result of altered endothelial glycosaminoglycan characteristics.

Increased tissue factor pathway inhibitor (TFPI) and coagulation in patients with insulin-dependent diabetes mellitus.

Recently, we found an increase in tissue factor pathway inhibitor (TFPI) activity in patients with insulin-dependent diabetes mellitus (IDDM). This increase in TFPI activity could be the result of increased thrombin formation and/or altered binding of TFPI to glycosaminoglycans. We studied TFPI activity (chromogenic assay) in relation to prothrombin F1 + 2 fragments and endogenous thrombin potential (ETP), in 46 IDDM patients, and 18 age and sex-matched healthy controls. Prothrombin, antithrombin and thrombomodulin were also determined. In IDDM patients, TFPI activity and F1 + 2 levels were significantly higher, while ETP, prothrombin antigen levels, and antithrombin activity were lower as compared to the controls. In IDDM patients with microalbuminuria, a manifestation of generalized angiopathy, TFPI activity, F1 + 2 and thrombomodulin levels were higher than in patients with only retinopathy or patients without complications. No correlation between TFPI activity, F1 + 2 levels and thrombomodulin was found, while TFPI activity was negatively correlated with ETP (r = -0.27). Microalbuminuria was significantly correlated with TFPI activity (r = 0.46), F1 + 2 (r = 0.56), and thrombomodulin (r = 0.52). In TFPI-depleted plasma, ETP increased, indicating that ETP is affected by TFPI. In conclusion, the increase in TFPI activity in IDDM patients may not be considered to be a reaction on a procoagulant state. It is hypothesized that vascular damage, leading to alterations in glycosaminoglycans, is in part responsible for the changes in TFPI activity, F1 + 2 levels and ETP.

Tissue factor pathway inhibitor activity in patients with IDDM.

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.

Lipoprotein(a) levels in relation to diabetic complications in patients with non-insulin-dependent diabetes.

The relationship between serum levels of lipoprotein(a) Lp(a)) and the presence of chronic diabetic complications was studied in 194 patients with non-insulin-dependent diabetes mellitus (NIDDM; 75 males, 119 females; age 66 +/- 11 years; duration of diabetes, 11 (range 1-35) years). They were taking various treatments (diet alone, oral hypoglycaemic agents and/or insulin). Metabolic status and prevalence of diabetic complications were assessed by detailed history, physical examination, laboratory analysis and ECG. Average metabolic control was moderate (HbA1c 8.2 +/- 1.7%). Median serum Lp(a) level was 183 U l-1 (range 8-2600 U l-1), which was significantly higher than in control subjects of comparable age (median 101; range 8-1747 U l-1; P < 0.05), while HDL-cholesterol levels were lower (1.14 +/- 0.38 vs. 1.35 +/- 0.35 mmol l-1; P = 0.001), and total cholesterol levels were comparable. No significant relationships between diabetes treatment or metabolic control and Lp(a) levels were observed. In the quartile of patients with the highest Lp(a) levels, total cholesterol and triglycerides were slightly higher (P < 0.05), whereas HDL-cholesterol was not different. With increasing Lp(a) levels, higher prevalences of preproliferative retinopathy and of coronary artery disease (CAD) were observed, but not of the other complications. No relationship was found between the degree of albuminuria and Lp(a) levels. We conclude that in NIDDM patients, Lp(a) levels are elevated compared with non-diabetic subjects, and that higher Lp(a) levels are associated with higher prevalences of CAD and of retinopathy.

Improved blood glucose control by insulin therapy in type 2 diabetic patients has no effect on lipoprotein(a) levels.

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean +/- SD: age 67 +/- 9 years, body mass index 26.1 +/- 4.4 kg m-2, median duration of diabetes 10 (range 1-37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 +/- 2.2 mmol l-1 to 8.4 +/- 1.8 mmol l-1 (p < 0.001), and HbA1c had fallen from 11.1 +/- 1.4% to 8.2 +/- 1.1% (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10%. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8-3050 mg l-1, vs 101, range 8-1747 mg l-1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.

Acute renal failure after cardiovascular surgery. Current concepts in pathophysiology, prevention and treatment.

Acute renal failure (ARF) is a serious complication of cardiovascular surgery and has a high mortality rate, especially with oliguria. It is usually caused by ischaemic injury of the kidney, resulting from inadequate perfusion. Certain risk factors which might lead to the development of ARF following open heart operations have been identified: age greater than 70 years; elevated pre-operative serum creatinine; low blood pressure during cardiopulmonary bypass; rate of haemolysis; a postoperative critical circulation. It is necessary to establish the diagnosis as soon as possible in order to institute corrective measures to prevent oliguric ARF. Once renal failure is established close control of hydration, solutes and potentially toxic metabolites is necessary. Early renal replacement therapy with proper nutritional support appears to improve survival.