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      Fibrinolysis Defect in Long-Term Hemodialysis Patients with Type 2 Diabetes mellitus and Its Relation to Metabolic Disorders

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          Background/Aims: Patients with chronic renal failure (CRF) secondary to diabetes mellitus show a high incidence of atherosclerosis with its thrombotic complications. Both CRF and type 2 diabetes mellitus (DM2) results in fibrinolysis defects causally related to atherogenesis and thrombogenesis. It is not well known whether or not and, if so, how fibrinolysis is altered in patients with both CRF and DM2. Our study was designed (1) to identify the fibrinolysis defect present in patients with DM2-mediated CRF and treated by long-term hemodialysis (DM2HD), and (2) to establish whether the fibrinolysis defect is related to the metabolic abnormalities observed in CRF or DM2. Methods: Sixteen DM2HD patients and 23 healthy individuals (HI) had their euglobulin clot lysis time (ECLT), and tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) activities (act) and concentrations (ag) assessed before and after standard fibrinolytic stimulus (i.v. administration of 0.4 µg/kg BW 1-deamino-8- D-arginine vasopressin, DDAVP) along with metabolic status markers. Results: DDAVP caused a significant shortening of ECLT, rises in tPA act and ag, and a significant decrease in PAI-1 act. PAI-1 ag declined significantly in HI, but not in DM2HD. A comparison of responses to DDAVP revealed the groups differed significantly in the change in PAI-1 ag. Whereas, in HI, PAI-1 ag decreased by 11.8 ng/ml, no decrease was seen in DM2HD (0.0 ng/ml) (p < 0.0001; medians given; unpaired Wilcoxon’s test). Stepwise regression analysis showed the change in PAI-1 ag was highly group-specific (DM2HD vs. HI, regression coefficient 21.22; partial correlation 0.58; p < 0.0001) and, also dependent on the serum concentrations of apolipoprotein A-I (–32.41; –0.46; p < 0.01) and homocysteine (0.35; 0.36; p < 0.05). Conclusions: Patients with type 2 DM and CRF on long-term hemodialysis have a fibrinolysis defect manifesting itself after standard fibrinolytic stimulus by an insufficient decrease in PAI-1 concentrations. The defect is related to decreased serum levels of apolipoprotein A-I and increased serum levels of homocysteine. The defect might be a factor contributing to accelerated atherosclerosis and thrombotic complications in these patients.

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          Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.

          Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean +/- SD, 3.28 +/- 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 +/- 0.71 g per liter in those who did not; P = 0.01), von Willebrand factor antigen (138 +/- 49 percent vs. 125 +/- 49 percent, P = 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 +/- 4.7 ng per milliliter vs. 10.0 +/- 4.2 ng per milliliter, P = 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P = 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease.
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            Hyperinsulinemia, Hyperglycemia, and Impaired Hemostasis

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              Angiographic severity and extent of coronary artery disease in patients with type 1 diabetes mellitus.

              Studies of the characteristics of coronary artery disease (CAD) in diabetic patients have shown conflicting results. Only 2 studies exploring the severity of CAD, specifically in type 1 diabetes, have been published, and neither of them has used computer-aided quantitative coronary angiography. This retrospective study comprised 64 (24 women and 40 men) type 1 diabetic patients and nondiabetic control subjects. To estimate the severity, extent, and overall "atheroma burden" of CAD, we used quantitative coronary angiographic-based segmental analysis of coronary angiograms. Type 1 diabetic patients had greater global severity (p < 0.001), global extent (p < 0.001), and global atheroma burden (p < 0.001) indexes than nondiabetic control subjects. Quantitative coronary angiographic-derived indexes of CAD were, on average, 1.4- to 4.3-fold higher in diabetic than in nondiabetic patients. These differences were particularly marked in women. We found that type 1 diabetic patients with a clinical indication for coronary angiography, especially women, have more severe, extensive, and distal type of CAD than individually matched nondiabetic control patients. Our findings, including a loss of sex difference for CAD among type 1 diabetic patients and a marked impact of type 1 diabetes in women, are not explained by established risk factors.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                December 2002
                07 October 2002
                : 22
                : 5-6
                : 429-436
                aDepartment of Internal Medicine I, Charles University Medical School, Pilsen, Czech Republic; bDepartment of Medicine, Keck’s School of Medicine, University of Southern California, Los Angeles, Calif., USA
                65270 Am J Nephrol 2002;22:429–436
                © 2002 S. Karger AG, Basel

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                Tables: 7, References: 54, Pages: 8
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