Atherogenic Lipoproteins Support Assembly of the Prothrombinase Complex and Thrombin Generation: Modulation by Oxidation and Vitamin E

Abstract

The importance of lipoproteins in the etiology of atherosclerosis is well established. Evidence is now accumulating to implicate thrombin in the pathogenesis of atherosclerosis. We have investigated whether atherogenic lipoproteins can support thrombin generation. In the absence of platelets or endothelial cells, both very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (LDL) support assembly of the prothrombinase complex and generation of thrombin. Thrombin generation (per μg of apolipoprotein) supported by VLDL was 19.4-fold greater than that supported by high-density lipoprotein (HDL), P < .00001, and 11.7-fold greater than that supported by LDL, P < .00001. Oxidation of LDL increased lipoprotein-supported thrombin generation 12-fold compared to unmodified LDL, P < .0001. We have shown that the phenomenon of lipoprotein-supported thrombin generation is mediated predominantly by specific phospholipids and is enhanced by oxidation of these phospholipids. The addition of vitamin E (α-tocopherol) markedly reduced the increase in thrombin generation observed after oxidation of LDL (822 ± 57 v 138 ± 47 nmol/L;P < .0001). These effects suggest that lipoproteins are important in the production of thrombin and that vitamin E may confer protection from the detrimental effects of lipoprotein oxidation by limiting thrombin formation. These results suggest that atherogenic lipoproteins are linked to the development of atherosclerosis in part by their capacity to support thrombin generation.

Apolipoprotein C‐III predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation

“…To our knowledge, this is the first study that demonstrates an independent association between apo C-III and thrombin generation. Remarkably, our results are consistent with the previous demonstration that thrombin generation supported by VLDL, rich in apo C-III, was about twelvefold greater than that supported by LDL and twentyfold greater than that supported by HDL [33]. Moreover, apo C-III has been demonstrated to stimulate monocyte activation [9] by means of Toll-Like Receptor 2 signalling [34] and these cells are known to be involved in tissue factor-dependent thrombin generation [35].…”

Redox‐regulation of haemostasis in hypoxic exercising humans: a randomised double‐blind placebo‐controlled antioxidant study

“…It is also known that oxidised lipoproteins support the assembly of the Va/Xa (prothrombinase) complex (Rota et al 1998) and as such increase thrombin generation, as indeed our findings corroborate. Furthermore, studies in patients with antiphospholipid syndrome, which promotes a hypercoagulable state, have demonstrated that coagulation is activated by oxidative stress via overexpression of monocyte tissue factor (Ferro et al 2003).…”

“…Previously, authors have suggested that the hypoxia-induced increase in thrombin generation was associated with oxidised low density lipoprotein (LDL-OX)-mediated increased assembly of the prothrombinase complex (Rota et al, 1998) and oxidative stress increased the bioactivity of factor VIII by an as of yet unknown mechanism (Koprivica et al 2011). The existing literature regarding the thrombogenicity of hypoxia remains conflicting and our findings collectively support those that state that hypoxia alone fails to alter blood coagulation (Andrew et al 1987;Crosby et al 2003;Hodkinson et al 2003;Fall et al 2011Fall et al , 2015.…”

Oxidized low‐density lipoprotein in inflammation‐driven thrombosis

“…However, it has been shown that OxLDL delays plasmatic coagulation in vitro [24], mediated through inhibition of FVIII, FIX and FXI activity [25]. Another group, however, described increased prothrombinase activity and thrombin generation caused by OxLDL [26]. Yet another group reported that OxPLs led to increased prothrombinase activity [27].…”