Von Willebrand Factor, ADAMTS13 and D-Dimer Are Correlated with Different Levels of Nephropathy in Type 1 Diabetes Mellitus

Abstract

We have investigated whether von Willebrand factor, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and D-Dimer were associated with different levels of renal function in patients with type 1 diabetes. Patients were classified according to level of renal function through estimated glomerular filtration rate: ≥90 and <130mL/min/1,73m2, n=52 (control group), ≥60 and <90mL/min/1,73m2, n=29 (mild renal dysfunction group), <60mL/min/1,73m2, n=28 (severe renal dysfunction group); and through urinary albumin excretion: normoalbuminuria, microalbuminuria and macroalbuminuria. Von Willebrand factor, ADAMTS13, and D-Dimer plasma levels were determined by enzyme-linked immunosorbent assay. ADAMTS13 activity was determined by fluorescence resonance energy transfer assay. Von Willebrand factor levels were increased in patients with mild (P=0.001) and severe (P<0.001) renal dysfunction as compared to the control group. ADAMTS13 levels were also increased in mild (P=0.029) and severe (P=0.002) renal dysfunction groups in comparison to the control group, while ADAMTS13 activity was increased only in the severe renal dysfunction group as compared to the control group (P=0.006). No significant differences were observed among the groups regarding von Willebrand factor/ADAMTS13 ratio. ADAMTS13 activity/ADAMTS13 levels ratio was reduced in patients with mild (P=0.013) and severe (P=0.015) renal dysfunction as compared to the control group. D-Dimer levels were increased in patients with mild (P=0.006) and severe (P<0.001) renal dysfunction as compared to the control group; it was also higher in patients with severe renal dysfunction as compared to the mild renal dysfunction group (P=0.019). Similar results were found for albuminuria classification. Increased von Willebrand factor, ADAMTS13, and D-Dimer levels and decreased ADAMTS13 activity/ADAMTS13 levels ratio are associated with renal dysfunction in patients with type 1 diabetes, suggesting that endothelial dysfunction and hypercoagulability are associated with nephropathy in type 1 diabetes.

ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice

“…Second, type 2 diabetes patients with diabetic nephropathy often have only partially reduced ADAMTS13 activity rather than severe ADAMTS13 deficiency. 10, 11, 14 The present study did not define whether partially reduced ADAMTS13 levels contribute to diabetic nephropathy exacerbation. Future studies will be required to determine the threshold of ADAMTS13 specific activity required to prevent exacerbated diabetic nephropathy.…”

“…10, 11, 14 We determined whether progression of diabetic nephropathy in streptozotocin-induced diabetes model would cause an increase in VWF levels associated with decreased ADAMTS13 specific activity. In WT diabetic mice, we found that plasma ADAMTS13 specific activity was markedly reduced by ≅46%, whereas plasma VWF levels were increased by 3.8 fold (P<0.05 vs. WT-non diabetic mice, Figure 1A&B).…”

“…Our findings are consistent with several population-based studies, which have observed low ADAMTS13 activity and high VWF antigen levels in in type 1 and type 2 diabetic patients affected with diabetic nephropathy. 10, 11, 14, 19, 20 The mechanisms by which ADAMTS13 specific activity is reduced in the setting of diabetes remain unclear. Possible mechanisms include: 1) reduced synthesis and secretion of ADAMTS13 by hepatic stellate cells in the liver; 2) increased ADAMTS13 consumption and/or incorporation into thrombi together with its substrate VWF, as observed in patients with acute MI; 21 3) loss of function due to inhibitory autoantibodies to ADAMTS13; 22 and 4) oxidative modification of ADAMTS13.…”

Effect of Vitamin D Status on Von Willebrand Factor and ADAMTS13 in Diabetic Patients on Chronic Hemodialysis

“…Endothelial dysfunction and hypercoagulability are involved in the development of cardiovascular complications observed in patients with DKD [23]. von Willebrand factor (vWF), a multimeric glycoprotein synthesized and stored in endothelial cells and platelets, plays an important role in platelet thrombi formation.…”

“…Increased plasma levels of vWF might reflect damage to endothelial cells and a hypercoagulability state and have been associated with diabetes and atherosclerosis [5]. Recent studies report that, in patients with DKD, the observed high risk of cardiovascular complications might be associated with increased plasma levels of vWF and reduced ADAMTS13 levels [23]; these decreased ADAMTS13 levels might cause the increased vWF levels [235]. Thus, vWF and ADAMTS13 seem to be involved in the relationship between diabetes mellitus, kidney disease, hypercoagulability, and atherosclerotic cardiovascular diseases.…”