Sailing Between Scylla and Charybdis: Oral Long-term Anticoagulation in Dialysis Patients

Thilo Krüger; Vincent Brandenburg; Georg Schlieper; Nikolaus Marx; Jürgen Floege

Disclosures

Nephrol Dial Transplant. 2013;28(3):534-541. 

In This Article

Vitamin K Antagonists and Vascular Calcification

Coumarins inhibit the vitamin K cycle by blocking the two enzymes (DT diaphorase and vitamin K epoxide reductase, VKOR) of this cycle. The subsequent endogenous vitamin K depletion results in an undercarboxylation, i.e. inactivation, of the vitamin K-dependent factors II, VII, IX and X in the liver and thus retards the coagulation cascade. However, carboxylation steps are also affected in extrahepatic tissues and target, amongst others, osteocalcin and matrix Gla protein (MGP). MGP is the most potent inhibitor of vascular calcification within the walls of large arteries. MPG knockout mice develop a dramatic calcification of the complete aortic wall and die due to a ruptured aorta at about 6–8 weeks of age.[36] Functional inactivation of MGP, i.e. undercarboxylation, can also be induced by warfarin and this too results in medial aortic calcification in rats.[37,38] In humans, Koos et al. demonstrated that the use of warfarin leads to accelerated calcification of the aortic valve in patients with mild or no CKD.[39] In comparison to the general population, the serum levels of inactive, i.e. uncarboxylated MGP, are increased in HD patients and the administration of vitamin K to HD patients is able to reduce this.[28] We also demonstrated that low levels of circulating carboxylated MGP predict an increased mortality in these patients.[40] Whether improved activation of MGP by supplementing vitamin K to HD patients will indeed retard the progress of vascular calcification is the subject of our planned randomized VitaVasK trial.

Another potential consequence of vitamin K antagonism is calciphylaxis (also termed calcific uraemic arteriolopathy). This rare but devastating and often lethal disorder is due to calcification and occlusion of cutaneous arteries and arterioles; it mostly affects patients with advanced CKD. In our German calciphylaxis registry, 45% of the affected patients had been taking vitamin K antagonists before development of calciphylaxis (unpublished data). In line with this, Japanese nationwide data on calciphylaxis patients noted an odds ratio of ~10 for warfarin usage and the development of calciphylaxis.[41]

Thus, two major vascular consequences, namely accelerated arterial medial and valvular calcification as well as the development of calciphylaxis, are linked to vitamin-K antagonism and may be much more pronounced in patients with advanced CKD.

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