Extrinsic coagulation pathway activation and metalloproteinase-2/TIMPs system are related to oxidative stress and atherosclerosis in hemodialysis patients.

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), together with extrinsic coagulation pathway activation and increased oxidative stress (SOX) have all been implicated as important factors in atherosclerosis and vascular remodelling. The aim of the present study was to investigate whether the MMPs/TIMPs system is associated with activation of the extrinsic coagulation pathway in conditions of increased SOX in hemodialysis (HD) patients. In HD patients, with and without cardiovascular disease (CVD), and in controls, we compared pre-dialysis levels of MMP-2, MMP-9,TIMP-1,TIMP-2; the markers of extrinsic coagulation pathway-tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F1+2 (F1+2); a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) and a surrogate of atherosclerotic disease-intima media thickness (IMT). Hemodialysis patients, particularly those with CVD, showed a significant increase in values of MMP-2/TIMPs, markers of the extrinsic coagulation pathway, Cu/Zn SOD and IMT as compared to controls. The markers of coagulation activation positively correlated with the MMP-2/TIMPs system, whereas they did not correlate with MMP-9. In addition, both MMP-2/TIMPs as well as extrinsic coagulation parameters were related to the prevalence of increased SOX, IMT and CVD. Multiple stepwise regression analysis showed that low TIMP-2 followed by increased Cu/Zn SOD and MMP-2 levels independently and significantly predicted elevated IMT on maintenance HD patients. In conclusion, our data suggest that the MMP-2/TIMPs system and an activated extrinsic coagulation pathway could cooperate in conditions of elevated SOX and could influence arterial remodeling resulting in the presence of CVD in haemodialysis patients.