Warfarin and Vascular Calcification

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Warfarin has recently been associated with an increased risk of stroke in ESRD patients with atrial fibrillation. This makes the decision whether to initiate warfarin therapy in dialysis patients with atrial fibrilltion anything but clear cut. Add to this the emerging evidence that it also promotes vascular calcification, and you have a real dilemma.
This latter side effect hinges on Matrix Gla protein, or MGP. In ESRD, vascular smooth muscle cells (VSMCs) undergo a phenotypic switch to take on the appearance of osteoblasts, in a well-described process thought to be driven by hyperphosphatemia. Once this has occurred, VSMCs lay down a protein matrix which can undergo calcification, similar to normal bone. MGP is an essential endogenous inhibitor of this process, mediated in part by it’s ability to bind calcium. This ability to bind calcium is a Vitamin K dependant process, explaining how warfarin may increase the risk of vascular calcification.
Warfarin has been linked to aortic valve calcification in both the general population and in ESRD, as well as calcific uremic arteriopathy in the latter. In fact, the odds ratio for severity of aortic valve calcification after 18 months of warfarin in ESRD was almost 4. Prospective trials are clearly needed, but for now, adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score > 2.

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