Vascular calcification: The price to pay for anticoagulation therapy with vitamin K-antagonists

Quantifying a Rare Disease in Administrative Data: The Example of Calciphylaxis

“…[3][4][5]25,26 Establishing temporal trends in calciphylaxis allows rigorous pharmacovigilance studies focused on therapeutics that are known to induce vascular calcification, e.g., vitamin D analogues, warfarin, calciumbased phosphate binders, and iron. [27][28][29] Accurate identification of calciphylaxis cases in a large administrative database such as the USRDS also offers the opportunity to study whether certain commonly used therapies in dialysis patients, such as cinacalcet, sevelamer, or statins, offer any protection against calciphylaxis. 25,30,31 Our study also provides fundamental epidemiological data, as future studies related to biomarkers, therapeutic target discovery, and clinical trials are planned for calciphylaxis.…”

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

“…Recent data imply that the intake of VKA involves effects beyond the well‐known inhibition of the vitamin K–dependent coagulation factors (F) II, VII, IX, and X 2. Experimental data suggest that VKA may decrease the activity of the vitamin K–dependent proteins matrix GIa protein (MGP) and growth arrest–specific gene 6 (Gas‐6) by inhibiting the γ‐carboxylation process 3. Unlike coagulation factors, which are synthesized and carboxylated within the liver, MGP and Gas‐6 are carboxylated within the vasculature 4.…”

New Perspectives for the Nutritional Value of Vitamin K in Human Health

“…Interestingly, approximately 50% of stage 5 CKD patients who develop calciphylaxis were on VKA therapy, which was proposed as one of the risk factors in the absence of severe disorders of calcium metabolism [9,38]. In the population-based Rotterdam study vitamin K2 intake was found inversely related to all-cause mortality and severe aortic calcification [39].…”

“…Interestingly, extra-hepatic Gla proteins have been shown to be present as incompletely γ-carboxylated forms in the majority of healthy adults [4,25], and thus the biological activity of these proteins could be considered sub-optimal. Since VKOR is a dithiol dependent enzyme known to be inhibited by 4-hydroxycoumarin anticoagulant drugs, such as warfarin, acenocoumarol, and phenprocoumon, the widely use of these oral anticoagulants acting as vitamin K antagonists (VKAs), has also been linked to unwanted side effects in several extra-hepatic tissues with adverse clinical outcomes [4,[7][8][9]11,12]. Remarkably, despite the long use of VKA the exact mechanism of inhibition of VKOR remains to be elucidated [26].…”

“…Vitamin K is an essential micronutrient acting as cofactor for the post-translational modification of vitamin K-dependent proteins (VKDPs), where specific glutamic acid (Glu) residues can be modified to calcium binding γ-carboxyglutamic acid (Gla) residues, through the action of γ-glutamyl carboxylase (GGCX) enzyme [6][7][8]. The use of vitamin K antagonists (VKAs) such as warfarin, known to influence the carboxylation of Glu residues of the coagulation factors in liver, has been shown to also impair the γ-carboxylation of extra-hepatic VKDPs, resulting in unwanted pathological side-effects in tissues such as bone and blood vessels [6,7,[9][10][11][12]. Recently, additional functions of vitamin K, such as anti-inflammatory, transcriptional regulator of osteoblastic genes, and inhibition of tumor progression, have been proposed to be mediated by a direct vitamin K effect rather than through VKDPs action [13,14].…”