Abstract
Background: Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease in the general population. We compared associations between vWF level and markers of inflammation as well as the effects of low molecular weight heparin (LMWH) in obese as compared to healthy human subjects.
Methods: Plasma samples were obtained from healthy volunteers (n = 32) and obese subjects (n = 12) before and after administration of a single subcutaneous (SC) dose of tinzaparin, given at a deep vein thrombosis (DVT) prophylaxis dose of 75 IU/kg once a day. These samples were analyzed for vWF and tumor necrosis factor-α (TNF-α) by ELISA. Also examined was the effect of different LMWH on the release of vWF from human umbilical vein endothelial cells (HUVEC) in response to various stimuli, such as oxidized low density lipoprotein (LDL) or endotoxin.
Results: Obese subjects showed higher plasma levels of TNF-α compared with normal-weight subjects. Regression analysis showed plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-α in these obese subjects. Tinzaparin, given at a prophylaxis dose for DVT (75 IU/kg, SC, QD), significantly reduced elevated plasma levels of endothelial dysfunction marker vWF associated with higher inflammatory TNF-α levels (P <0.01). HUVEC, when treated with oxidized LDL or endotoxin, demonstrated a significant elevation of vWF release into the medium in a time-dependent manner. Tinzaparin and enoxaparin significantly reduced this increased vWF release from HUVEC in the media.
Conclusion: Plasma values of vWF and TNF-α are higher in obese than in normal-weight individuals. Treatment with tinzaparin lowers plasma levels of TNF-α in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones because of the higher levels of circulating TNF-α. Tinzaparin reduced vWF levels in these obese subjects.
Table 1. Effect of Tinzaparin (75 IU/kg, SC, QD) on Plasma vWF in Obese and Normal-Weight Subjects
Table 2. Effect of Tinzaparin (75 IU/kg, SC) on Plasma TNF-α in Obese and Normal-Weight Subjects
Subjects Mean Plasma vWF (IU/mL) ± SD Pre-Tinzaparin Mean Plasma vWF (IU/mL) ± SD Post-Tinzaparin (2 h) * P <0.05 obese versus normal-weight subjects before treatment with tinzaparin; †P <0.01 post- versus pre-tinzaparin; vWF = von Willebrand factor. Normal body weight (n = 32) 0.44 ± 0.15 0.36 ± 0.12 Obese (n = 12) 0.68 ± 0.20* 0.29 ± 0.11† Subjects Mean Plasma TNF- α (pg/mL) ± SD Pre-Tinzaparin Mean Plasma TNF- α (pg/mL) ± SD Post-Tinzaparin * P <0.05 obese compared with normal-weight subjects before treatment with tinzaparin; †P <0.01 post- compared with pre-tinzaparin; TNF-α = tumor necrosis factor-α. Normal body weight (n = 32) 1.68 ± 0.55 1.37 ± 0.33 Obese (n = 32) 2.82 ± 0.38* 1.45 ± 0.25†
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