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      Low Plasma Activated Protein C-Protein C Inhibitor Complex Concentration Is Associated with Vascular Access Failure in Hemodialysis Patients


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          Background: Vascular access failure is a common cause of morbidity in patients with end-stage renal failure on hemodialysis (HD). Activation of the coagulation system and formation of a thrombus play important roles in recurrent arteriovenous fistula/graft (AVFG) failure. Thrombin in complex with thrombomodulin (TM) activates the anticoagulant protein C and creates activated protein C (APC), which is subsequently inactivated by the protein C inhibitor (PCI). The plasma concentration of the complex between APC and PCI (P-APC-PCI complex) is increased in hypercoagulable states and is therefore a sensitive indicator of the degree of activation of blood coagulation. Methods: Thirty-five HD patients dialyzed through a functioning AVFG were studied. The period of patency of AVFGs was recorded. Blood was drawn before and after the HD session for the analysis of the APC-PCI complex, soluble TM concentration and activity, von Willebrand factor antigen and homocysteine. Results: Patients with frequent AVFG failures (n = 8) had a significantly lower level of P-APC-PCI complex (median 0.09 µg/l) than those with less frequent AVFG failures (median 0.18 µg/l; n = 27; p = 0.04). No other significant differences were found between the groups. Conclusion: Thus, a low level of P-APC-PCI complex may be associated with an increased risk of AVFG failure in HD patients. Further prospective studies are needed to confirm these results and to evaluate the possibility of prophylactic measures.

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          Most cited references22

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          Hemodialysis vascular access morbidity in the United States.

          Extensive morbidity related to hemodialysis vascular access exists among end-stage renal disease (ESRD) patients, but the risk factors for this morbidity have not been extensively studied. Medicare ESRD patient data were obtained from 1984, 1985, and 1986. Hospitalization for vascular access morbidity (ICD-996.1, 996.6, or 996.7) was analyzed among prevalent patients and, using survival analysis, among incident patients to assess sex, age, race, and underlying cause of renal failure as risk factors. We found that 15 to 16% of hospital stays among prevalent ESRD patients were associated with vascular access-related morbidity. Black race, older age, female sex, and diabetes mellitus as a cause of kidney failure were all independent risk factors for access-related morbidity. The rate ratio comparing Blacks to Whites was 1.12 (95% C.I., 1.09, 1.16); > 64 years to 20 to 44 years, 1.53 (1.46, 1.59); men to women, 0.81 (0.79, 0.84); and diabetes to glomerulonephritis, 1.29 (1.24, 1.35). We conclude that hemodialysis vascular access malfunction causes much hospitalization among ESRD patients. Women, Blacks, the elderly, and diabetics appear to be at particularly high risk, and additional studies are needed to understand these patterns.
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            Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma.

            Endothelial cell membrane-bound thrombomodulin (TM) plays a critical role as a cofactor in the protein C pathway, important in regulating coagulation as well as inflammation. Heterogeneous soluble TM fragments circulate in the plasma and are found at increased levels in various diseases such as cardiovascular disease and diabetes, and in ischemic and/or inflammatory endothelial injuries. The anticoagulant function of these soluble fragments has not been measured in healthy individuals or in patients. Using an immobilized monoclonal antibody against TM and a microtiter plate format, an assay was designed to capture the soluble TM fragments in plasma and measure their cofactor activity in the thrombin-mediated activation of protein C. In addition, soluble TM antigen levels were measured by enzyme-linked immunosorbent assay. Both assays were used to investigate a group of healthy blood donors. TM fragments released into plasma were shown to retain significant cofactor activity, and reference intervals for healthy men and women were established. Furthermore, a statistically significant correlation was observed between soluble TM antigen levels and soluble TM cofactor activity. This notwithstanding, soluble TM activity only accounted for a minor part of all variation in soluble TM antigen levels (R2 = 22% in men and R2 = 16% in women).
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              Vascular access for hemodialysis. Patency rates and results of revision.

              Over a 4-year interval, 324 arteriovenous conduits were created in 256 patients with end-stage renal disease as access for chronic hemodialysis. These included 154 Cimino fistulae, 163 polytetrafluoroethylene (PTFE) grafts, and seven miscellaneous grafts. Satisfactory patency rates were demonstrated for as long as 4 years for both Cimino fistulae and PTFE grafts by life-table analysis. Failures of Cimino fistulae usually occurred early in the postoperative period, secondary to attempts to use inadequate veins. Thrombosis caused the majority of PTFE graft failures and was generally the result of venous stenosis. Correction of such venous stenosis is mandatory to restore graft patency and can result in prolonged graft survival.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                November 2008
                27 October 2008
                : 110
                : 3
                : c151-c157
                Departments of aNephrology and bClinical Chemistry, University Hospital, Lund, and cDepartment of Clinical Chemistry, University Hospital, Malmö, Sweden
                166606 Nephron Clin Pract 2008;110:c151
                © 2008 S. Karger AG, Basel

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                : 19 December 2007
                : 03 July 2008
                Page count
                Figures: 1, Tables: 4, References: 30, Pages: 1
                Original Paper

                Cardiovascular Medicine,Nephrology
                Activated protein C-protein C inhibitor complex,Vascular access failure,Hemodialysis patients


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