Vascular calcification is a strong independent risk factor for mortality. Vitamin K antagonists (VKA), prescribed to patients to reduce recurrent thrombosis, have undesired side effects by promoting vascular calcification. Here, we aimed to investigate the effects of long-term VKA treatment on vascular calcification, and the possible atherogenic and thrombogenic consequences of calcification.
Atherogenesis was investigated in male and female Apoe-/- mice receiving Western type diet, with or without warfarin for 6-18 weeks. Primary human vascular smooth muscle cells (VSMC) were cultured in the presence or absence of calcification and thrombogenicity was examined.
In mice, long-term VKA treatment significantly increased calcification and atherosclerotic plaque size. The VKA-induced calcification correlated with uncarboxylated MGP in the plaque, indicating a vitamin K-dependent mechanism. Additionally, plaque calcification correlated with atherosclerosis progression. Whilst VKA induced anticoagulation correlates with calcification, it also increased factor IXa:antithrombin levels. Interestingly, VKA-treated patients with vascular calcification had increased IXa:antithrombin plasma levels as compared to VKA-treated patients without vascular calcification. These findings suggest that vascular calcification contributes to a prethrombotic state. This notion was supported by in vitro experiments using control or calcified VSMC. Calcified VSMC displayed increased fibrin formation when superfused with whole blood under flow than non-calcified VSMC. Inhibitors of either the intrinsic or extrinsic coagulation pathways significantly reduced platelet aggregation and fibrin formation of calcified VSMC.
Taken together, these findings indicate that the anticoagulant VKA can give rise to a prethrombotic state by aggravating atherosclerosis and vascular calcification, thereby promoting activation of the coagulation cascade locally.

04 - LONG-TERM VITAMIN K ANTAGONIST TREATMENT INDUCES CALCIFICATION AND ATHEROSCLEROTIC PLAQUE PROGRESSION, PROMOTING A PRETHROMBOTIC STATE.