The vitamin K antagonist, warfarin, is the most commonly prescribed oral anticoagulant. Use of warfarin is associated with an increase in systemic calcification, including in the coronary and peripheral vasculature. This increase in vascular calcification is due to inhibition of the enzyme matrix gamma-carboxyglutamate Gla protein (MGP). MGP is a vitamin K-dependent protein that ordinarily prevents systemic calcification by scavenging calcium phosphate in the tissues. Warfarin-induced systemic calcification can result in adverse clinical effects. In this review article, we highlight some of the key translational and clinical studies that associate warfarin with vascular calcification.
Vascular calcification plays a key role in the pathophysiology of coronary artery disease, ischemic stroke, and peripheral arterial disease. Commonly recognized risk factors for vascular calcification include hypertension, diabetes, increasing age, chronic kidney disease, cigarette smoking, and systemic inflammation. Treatment with vitamin K antagonists such as warfarin is associated with vascular calcification, even when other risk factors are controlled.
Systemic calcification has adverse clinical implications. Developments in basic science have uncovered mechanisms responsible for increased systemic calcification.
Mechanisms of Vascular Calcification
Inflammation, hyperlipidemia, and other factors cause vascular smooth muscle cells to lose their contractile ability and differentiate into osteoblast-type cells. These factors lead to genetic changes, with upregulation of transcription factors such as the bone morphogenetic proteins, osterix, and core binding factor-α1.
To prevent tissue calcification, there are numerous protective inhibitory factors, such as osteopontin and osteoprotegerin. One of these protective factors is matrix gamma-carboxyglutamate Gla protein (MGP), a highly insoluble protein synthesized by vascular smooth muscle cells. MGP is an 84-amino acid protein in the Gla family that has been linked to vascular calcification. MGP functions via 5 unusual gamma-carboxyglutamate residues that bind calcium phosphate, preventing calcification at the cellular level. Like other Gla proteins, such as the procoagulant factors II, VII, IX, and X, and anticoagulant factors protein C and S, MGP must undergo posttranslation modification into its active form. The posttranslation carboxylation reaction requires vitamin K as a cofactor, and in the setting of vitamin K deficiency, MGP cannot be converted to its active form.
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-Timothy J. Poterucha, MD, Samuel Z. Goldhaber, MD
This article originally appeared in the June 2016 issue of The American Journal of Medicine.
