title: Warfarin accelerates ectopic mineralization in Abcc6(-/-) mice: clinical relevance to pseudoxanthoma elasticum.
abstract: Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. Warfarin, a commonly used anticoagulant, is associated with increased mineralization of the arterial blood vessels and cardiac valves. We hypothesized that warfarin may accelerate ectopic tissue mineralization in PXE, with clinical consequences. To test this hypothesis, we developed a model in which Abcc6(-/-) mice, which recapitulate features of PXE, were fed a diet supplemented with warfarin and vitamin K1. Warfarin action was confirmed by significantly increased serum levels of oxidized vitamin K. For mice placed on a warfarin-containing diet, quantitative chemical and morphometric analyses revealed massive accumulation of mineral deposits in a number of tissues. Mice fed a warfarin-containing diet were also shown to have abundant uncarboxylated form of matrix Gla protein, which allowed progressive tissue mineralization to ensue. To explore the clinical relevance of these findings, 1747 patients with PXE from the approximately 4000 patients in the PXE International database were surveyed about the use of warfarin. Of the 539 respondents, 2.6% reported past or present use of warfarin. Based on the prevalence of PXE (approximately 1:50,000), thousands of patients with PXE worldwide may be at risk for worsening of PXE as a result of warfarin therapy.
authors: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Qiaoli
authors: Q
authors: Li
authors: Haitao
authors: H
authors: Guo
authors: David W
authors: DW
authors: Chou
authors: Dominic J
authors: DJ
authors: Harrington
authors: Leon J
authors: LJ
authors: Schurgers
authors: Sharon F
authors: SF
authors: Terry
authors: Jouni
authors: J
authors: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020405:Dermis / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008903:Minerals / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009928:Organ Specificity / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism; D010758:Phosphorus / Q000097:blood; D011561:Pseudoxanthoma Elasticum / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology*; D014812:Vitamin K / Q000097:blood; D014859:Warfarin / Q000009:adverse effects* / Q000097:blood; D055114:X-Ray Microtomography; D000097568:Matrix Gla Protein
chemical_list: D018528:ATP-Binding Cassette Transporters; D002118:Calcium; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D008274:Magnesium; D008903:Minerals; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010710:Phosphates; D010758:Phosphorus; D014812:Vitamin K; D014859:Warfarin; D000097568:Matrix Gla Protein; C504743:Abcc6 protein, mouse