Elsevier

Blood Reviews

Volume 26, Issue 4, July 2012, Pages 155-166
Blood Reviews

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

https://doi.org/10.1016/j.blre.2012.03.002Get rights and content

Abstract

Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, however, that VKA inhibit not only post-translational activation of vitamin K-dependent coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins thereby eliciting undesired side-effects.

Vascular calcification is one of the recently revealed side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. Mechanistic understanding of vascular calcification is essential to improve VKA-based treatments of both thrombotic disorders and atherosclerosis. This review addresses vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis.

Introduction

Anticoagulant drugs are used for prevention and treatment of arterial and venous thromboembolic disorders. For many decades vitamin K-antagonists (VKA) were the only drug of choice for long-term treatment.1 Common inconvenient effects of VKA include unpredictable pharmacokinetics and pharmacodynamics, drug and food interactions, slow onset and offset of action, considerable inter-individual and intra-individual variability in dose response and narrow therapeutic window. In addition, frequent laboratory monitoring and dose adjustments are needed to keep patients within the INR (International Normalized Ratio) target range.2 Furthermore, the use of VKA for long-term anticoagulant treatment extents to extra-hepatic vitamin K-dependent proteins. Matrix Gla protein (MGP) is a vitamin K-dependent protein involved in the inhibition of calcification.3 VKA treatment inhibits the carboxylation of MGP, subsequently inhibiting its function and thereby accelerating vascular calcification.[4], [5] After more than 30 years of research new compounds (Factor Xa inhibitors; e.g. rivaroxaban, apixaban and Factor IIa inhibitors; e.g. dabigatran) have been introduced.[6], [7] These new drugs may provide an alternative for numerous well documented draw-backs associated with the use of VKA. This review focuses on the effects of VKA, their role in vascular calcification and the potential of new oral anti-coagulants.

Section snippets

Vitamin K

Discussing VKA in a review cannot be done without giving a background on vitamin K. Vitamin K was discovered by the Danish scientist Hendrik Dam in the early 1930s.8 During his research on cholesterol metabolism he observed severe subcutaneous and intramuscular hemorrhages in chickens reared on a fat-poor diet. However, substituting the diet with cholesterol did not rescue the bleeding phenomenon. It turned out that the fat-fraction contained a micronutrient that is responsible for normal blood

Vitamin K-antagonists

There are only few reviews dealing with the history of VKA, and one of the best dates from decades ago in which Link described the discovery of VKA.36 VKA were discovered in the early 1920s when malady of cattle involving fatal bleeding showed up almost simultaneously in the area of Wisconsin.37 Schofield found that cattle that had eaten spoiled hay and were being dehorned, lost clotting power resulting in fatal hemorrhages. Therefore the disease was called sweet clover disease. Roderick showed

Coagulation

Our knowledge about the blood coagulation system has expanded tremendously in the last 60 years shifting from single intrinsic and extrinsic pathways to a more all-encompassing model. Many of the coagulation factors were identified through detailed studies on individual patients having a severe hereditary bleeding tendency. It was in the mid-1950s a unified nomenclature was desired for the coagulation factors that were independently given by several groups who studied different properties and

Vascular calcification

The first observed case of vascular calcification dates from over 5000 years.[87], [88] For decades vascular calcification was regarded as a passive process, an inevitable consequence of aging and disease. Today we appreciate vascular calcification as a complex and actively regulated process involving cells and proteins acting as catalysts and inhibitors.[69], [89], [90], [91] Vascular calcification can occur at distinct sites of the vasculature; the heart valves, the tunica media and tunica

Vitamin K and vitamin K-dependent proteins in vascular calcification

Vascular calcification is independently associated with increased cardiovascular mortality and morbidity.[116], [117], [118], [119] The amount of vascular calcification, as measured and quantified by multi-slice computed tomography (MSCT) is an important predictor of all-cause mortality, vascular complications and myocardial infarctions.[120], [121], [122] Contrarily, ex vivo examination of the mechanical properties of plaques have put forward the hypothesis that large calcifications stabilize

Clinical importance of VKA in vascular calcification

Although already demonstrated in experimental animals in the mid 1990s, it took until 2004 before the first study in humans revealed an effect of VKA on vascular calcification.161 Today, more studies have been published describing the effect of VKA use on vascular calcification (Table 1). It was our group that tested the hypothesis that VKA in patients increase vascular calcification.161 In a collaboration we selected patients undergoing valvular surgery whom were willing to donate the explant

VKA and novel oral anticoagulants: future perspectives

Atrial fibrillation is the predominant indication for long term anticoagulant treatment. According to atrial fibrillation-guidelines, indication for long anticoagulant treatment is based on the stroke risk, which can be estimated using the CHADS2 score.194 Major trials have been designed to test whether direct thrombin or Factor Xa inhibitors are comparable to VKA with respect to efficacy.[195], [196], [197] In the RE-LY trail 18,113 subjects with AF were enrolled and were randomly assigned to

Conclusion

Even though first considered as clinically irrelevant, vascular calcification has been emerged as a strong and independent risk factor for cardiovascular morbidity and mortality. A large number of observational patient studies strongly suggest a causal role of VKA in arterial and valvular calcification. Although based on indirect evidence, it is suggested that the use of VKA is potentially harmful in some patient populations. As new direct anticoagulation therapy is emerging, preclinical and

Conflict of interest

No conflicts of interest to declare.

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