Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?

Abstract

Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.

Keywords: COPD; Cardiovascular diseases; Desmosine; Elastin; Matrix Gla protein; Vascular calcification; Vitamin K; Vitamin K antagonists.

Fig. 1

Proposed mechanisms that could be responsible for vitamin K deficiency. Low vitamin K consumption and use of vitamin K antagonists induce vitamin K deficiency. It is likely that polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene associated with low vitamin K recycling rates predispose to vitamin K deficiency. Accelerated elastin degradation, due to a protease/antiprotease imbalance, leads to elastin calcification and subsequently to an increased synthesis of matrix Gla protein, which needs to be activated by vitamin K. This increased vitamin K demand might also cause a vitamin K deficit

Fig. 2

Vitamin K cycle. Food-derived vitamin K first needs to be converted into the active metabolite vitamin K hydroquinone (KH₂). During the activation process of vitamin K-dependent proteins, the cofactor KH₂ is converted into vitamin K epoxide (KO). Subsequently, inactive KO has to be reduced, first into vitamin K and then into KH₂. These two reduction steps are executed by the enzyme vitamin K epoxide reductase (VKOR). VKAs are specific inhibitors of VKOR

Fig. 3

Triage theory. The triage theory implies that in case of mild vitamin K deficiency the coagulation factors are still activated by vitamin K, however, the anticoagulation protein S in the vascular wall and matrix Gla protein are insufficiently activated. This will lead to both increased thrombosis risk and elastin calcification. Elastin calcification causes elastin degradation and vice versa. Elastin degradation in the lungs leads to lung emphysema. Vascular calcification begins at the elastin fibers in the vascular walls. Only in case of severe vitamin K deficiency, coagulation factors are also insufficiently activated leading to increased bleeding tendency