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Mobile intracardiac calcinosis: risk of thromboembolism in patients with haemodialysed end stage renal disease
  1. Division of Cardiovascular Medicine
  2. University of Cambridge
  3. Addenbrooke's Hospital (ACCI level 6)
  4. Hills Road
  5. Cambridge CB2 2QQ, UK

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    Editor,—Tsuchihashi and colleagues describe a number of interesting cases of mobile cardiac calcinosis in dialysis patients complicated by systemic thromboembolism.1However, in their discussion of possible pathophysiological mechanisms they fail to mention the possible roles of a number of calcification regulatory proteins called Gla proteins. This is a potentially important omission as it may affect management decisions regarding anticoagulation with warfarin.

    Work from our laboratory and others has revealed that calcification in the vasculature is not simply a passive degenerative process as was previously thought.2 3 On the contrary it seems to be a highly complex and regulated process as in bone. Attention has focused on a number of proteins which appear to have regulatory roles during the calcification process and in particular on a group of these proteins known as Gla proteins.4 These Gla proteins are so named because they contain an uncommon amino acid—gamma carboxyglutamic acid (Gla)—formed by a vitamin K dependent post-translational modification of specific glutamic acid residues. The Gla residues appear to confer calcium binding properties to these proteins. One of the Gla proteins—matrix Gla protein—is thought to act as an inhibitor of calcification since it has been found in intimate association with areas of calcification, and mice lacking this gene have rampant vascular calcification.5

    Since metabolic defects in chronic renal failure do not fully explain the presence of extraskeletal calcification, a role for these calcification regulatory proteins is clearly possible. In addition there is in vitro as well as in vivo data from both humans and rats that inhibition of the vitamin K dependent process of Gla residue formation by warfarin may be deleterious, leading to an increase in calcification.6-8

    We feel there are sufficient data to exercise caution in the use of warfarin for the prevention of thromboembolism in the presence of critical extraskeletal and vascular calcification such as in the cases described by Tsuchihashi and colleagues, where any further increase in calcification could potentially be very harmful. Alternative anticoagulation strategies such as low molecular weight heparins may be more prudent until the basic mechanisms underlying the regulation of calcification are better understood. Whether long term warfarin treatment in general leads to any adverse effects such as increases in arterial, aortic or mitral annular calcification is worthy of investigation.


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    As pointed out by Farzaneh-Far and colleagues, many heterogeneous factors such as non-collagenous proteins (Gla protein and vitronectin in atherosclerosis plaques; osteopontin, vitronectin and osteocalcin in cardiac valve calcification), hypertension and aging, diabetes, excess vitamin D3 use, and calcium and phosphate imbalance through hypo- or hyperparathyroidism has been postulated as a possible cause of rapid calcinosis of the cardiovascular system in end stage renal disease.1-1-1-3 Recently, Price and colleagues in rats1-4 and Coates and colleagues in patients with calcific uraemic arteriopathy1-5 reported the possibility of warfarin related cardiovascular calcification in relation to non-collagenous proteins, Gla.

    We do think that the possible contributions of non-collagenous proteins to the rapid cardiovascular calcifications in end stage renal disease should not be neglected in our case studies; however, warfarin has not been prescribed in our cases before obtaining echocardiographic diagnosis. Therefore, warfarin use will not be the main cause of rapid calcinosis, at least in our series of cases. Moreover, in case 2 of our study,1-6 a surgical specimen revealed fresh red thrombus attaching to cardiac calcinosis, and any kind of anticoagulation treatment will be essential clinically for preventing short term thromboembolism. Indeed, low molecular weight heparin might be a better therapeutic option in these circumstances, but it also has a limitation in long term clinical use. At this point, monitoring calcium–phosphate imbalance and the changes of calcinosis size, warfarin use for preventing thromboembolism will be the most conventional drug treatment in cardiac calcinosis of end stage renal disease. Further studies should be conducted on the cause of rapid cardiac calcinosis and the possibility of warfarin having a deteriorating effect on cardiovascular calcinosis.


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