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Warfarin; rat poison or medicine at the same time
The story of the discovery of heparin and warfarin.
Wardrop D, Keeling D. Br J Haematol. 2008 Jun;141(6):757-63. Epub 2008 Mar 18.
Oxford Haemophilia and Thrombosis Centre, Oxford Radcliffe Hospitals, Oxford, UK.
Heparin and coumarins have been the mainstay of anticoagulant therapy throughout our working lives. As we stand on the threshold of a new era of anticoagulants it is timely to look back upon their discovery and development. Both have fascinating stories to tell.
Jay McLean claimed to have discovered heparin whilst a medical student, although this is disputed. The story of warfarin leads us from a mysterious haemorrhagic disease of cattle to the development of a rat poison which became one of the most commonly prescribed drugs in history. Many people were involved in both stories and we owe them all a debt of gratitude.
Effects of warfarin on blood pressure in men with diabetes and hypertension - a longitudinal study.
Lim MA, Shafique S, See SY, Khan FN, Parikh CR, Peixoto AJ.
Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA .J Clin Hypertens (Greenwich). 2007 Apr;9(4):256-8.
Warfarin causes extensive vascular calcification leading to increased systolic blood pressure and pulse pressure in rats, may be associated with increased valvular and coronary calcifications in man, and possibly worsens hypertension in high-risk patients, particularly in those with diabetes mellitus or uncontrolled hypertension. The authors evaluated blood pressure and intensity of antihypertensive therapy over 36 months in a cohort of 58 patients with diabetes and hypertension on warfarin and 58 control subjects with diabetes and hypertension not on warfarin. The results demonstrate that warfarin therapy at conventional doses does increase systolic blood pressure or pulse pressure in patients with diabetes and hypertension.
Warfarin and aortic valve calcification in hemodialysis patients.
Holden RM, Sanfilippo AS, Hopman WM, Zimmerman D, Garland JS, Morton AR.
Division of Nephrology, Queen's University, Kingston, Ontario, Canada. holdenr@kgh.kari.net J Nephrol. 2007 Jul-Aug;20(4):417-22.
BACKGROUND: This retrospective cohort study was designed to determine the association between long-term exposure to warfarin and severity of aortic valve (AV) calcification in hemodialysis (HD) patients.
METHODS: One hundred and eight HD patients underwent a study-specific echocardiogram. A grading scheme was used to classify AV calcification as none, mild, moderate and severe. Demographic, biochemical and medication data were abstracted by chart review.
RESULTS: One hundred and eight subjects were enrolled. A minority had no calcification (n=17, 15.7%), the majority had mild calcification (n=62, 57.4%), and fewer had calcification rated as moderate (n=16, 14.8%) or severe (n=13, 12%). Dialysis vintage was associated with severity of AV calcification (p=0.04). The 18 subjects with long-term warfarin exposure (36.7 +/- 19.7 months) were more likely to have severe AV calcification (p=0.04). The odds ratio of falling into a higher category of AV calcification following 18 months of warfarin was 3.77 (95% confidence ratio, 0.97-14.70; p=0.055). There was an association between lifetime months of warfarin exposure and severity of AV calcification (p=0.004) that was independent of dialysis vintage, calcium and calcitriol intake.
CONCLUSIONS: The data suggest that warfarin may be associated with severity of AV calcification in HD patients and support the need for prospective studies.
Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification.
Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, Weissberg PL, Proudfoot D. J Thromb Haemost. 2007 Dec;5(12):2503-11. Epub 2007 Sep 10
Cardiovascular Research Institute Maastricht and VitaK, University of Maastricht, Universiteitssingel 50, Maastricht, The Netherlands. l.schurgers@bioch.unimaas.nl
BACKGROUND: Matrix Gla protein (MGP) is a small vitamin K-dependent protein containing five gamma-carboxyglutamic acid (Gla) residues that are believed to be important in binding Ca(2+), calcium crystals and bone morphogenetic protein. In addition, MGP contains phosphorylated serine residues that may further regulate its activity. In vivo, MGP has been shown to be a potent inhibitor of vascular calcification; however, the precise molecular mechanism underlying the function of MGP is not yet fully understood.
METHODS AND RESULTS: We investigated the effects of MGP in human vascular smooth muscle cell (VSMC) monolayers that undergo calcification after exposure to an increase in Ca(2+) concentration. Increased calcium salt deposition was found in cells treated with the vitamin K antagonist warfarin as compared to controls, whereas cells treated with vitamin K(1) showed decreased calcification as compared to controls. With conformation-specific antibodies, it was confirmed that warfarin treatment of VSMCs resulted in uncarboxylated (Gla-deficient) MGP. To specifically test the effects of MGP on VSMC calcification, we used full-length synthetic MGP and MGP-derived peptides representing various domains in MGP. Full length MGP, the gamma-carboxylated motif (Gla) (amino acids 35-54) and the phosphorylated serine motif (amino acids 3-15) inhibited calcification. Furthermore, we showed that the peptides were not taken up by VSMCs but bound to the cell surface and to vesicle-like structures.
CONCLUSIONS: These data demonstrate that both gamma-glutamyl carboxylation and serine phosphorylation of MGP contribute to its function as a calcification inhibitor and that MGP may inhibit calcification via binding to VSMC-derived vesicles.
Vitamin K-dependent proteins, warfarin, and vascular calcification.
Danziger J. Clin J Am Soc Nephrol. 2008 Sep;3(5):1504-10. Epub 2008 May 21.
Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. jdanzige@bidmc.harvard.edu
Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.
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