Warfarin-Induced Vasculopathy

Abstract

The widespread use of warfarin for the prevention and treatment of thrombotic disorders involving the arterial and venous circulatory systems, coupled with world-wide drug availability and clinical use for greater than 60 years, provides ample opportunity to study its effects-both positive and negative. One area of emerging interest and considerable clinical relevance is warfarin-induced vasculopathy. Vascular calcification commonly accompanies atherosclerosis and is caused by the deposition of basic calcium phosphate crystals in a highly regulated process similar to bone formation (reviewed in reference 1). Vascular calcification has been described in several forms, including small crystal deposits in the neointima and large areas within advanced atherosclerotic plaques. It is the latter form that pretends a heightened propensity for cardiovascular morbidity and mortality [2–5]. Emerging data support vascular calcification as an active participant in atherogenesis. Nadra and colleagues [6] showed that human macrophages internalize basic calcium phosphate crystals, which in turn, triggers the release of inflammatory cytokines (TNF-a, Il-1, Il-v) in sufficient quantities to activate endothelial cells and promote leukocyte capture under shear flow. The release of TNF-a is of particular important in vascular calcification because it promotes osteoblast differentiation and calcification of vascular cells. Protein kinase C appears to be a key regulator of basic calcium phosphate-induced TNF-a release. Matrix c-carboxyglutamic acid (Gla) protein (MGP) a vitamin K-dependent protein is a potent in vivo inhibitor of arterial calcification. Its 5 Gla residues are formed in a post-translational carboxylation reaction in which vitamin K functions as an essential cofactor. Accordingly, the presence of Gla residues is critical for MGP function. Using sections of human carotid arteries, Schurgens and colleagues showed that conformation-specific antibodies against MGP detected functional protein around elastin fibers in the tunica media of healthy vessels. Under-carboxylated protein was not detected in normal tissue samples; however it was found in high concentrations within regions of calcification obtained from atherosclerotic tissue sections (Fig. 1–3) [7]. Given the important role of MGP and vitamin K in the prevention of calcium deposition, 3 factors potentially influencing arterial calcification should be considered: [1] the level of MGP expression; [2] vitamin K status; and [3] mutations/polymorphisms affecting the activities of either c-glutamyl carboxyloase or vitamin K epoxide reductase complex—a protein involved in the recycling of vitamin K. In a large association study, polymorphisms of the VKORC1 gene (CC and CT genotypes) conferred nearly twice the risk of vascular events (stroke, coronary artery disease, aortic dissection) and were associated with lower levels of osteocalcin (a regulator of bone metabolisms) and Protein Induced in Vitamin K Absence or Antagonism II (PIVKA-II, a des-c-carboxy prothrombin) than those with TT genotypes [8]. R. C. Becker (&) Duke University Medical Center, Durham, NC, USA e-mail: BECKE021@dcri.duke.edu J Thromb Thrombolysis (2007) 23:79–81 DOI 10.1007/s11239-006-9021-8