Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification

Abstract

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.

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

“…Experimental data suggest that VKA may decrease the activity of the vitamin K–dependent proteins matrix GIa protein (MGP) and growth arrest–specific gene 6 (Gas‐6) by inhibiting the γ‐carboxylation process 3. Unlike coagulation factors, which are synthesized and carboxylated within the liver, MGP and Gas‐6 are carboxylated within the vasculature 4. Increased levels of undercarboxylated MGP have been associated with vascular calcification 5.…”

“…Increased levels of undercarboxylated MGP have been associated with vascular calcification 5. The deficiency of active MGP and Gas‐6 provokes cell death, decreased contractility of vascular smooth muscle cells, and accelerated vascular calcification 4, 6. Studies have also demonstrated that VKA therapy is associated with vascular calcification 7, 8.…”

Warfarin and heterotopic ossification: good, bad or ugly?

“…In contrast, many studies have demonstrated that warfarin can induce cardiovascular calcifications. 3 Besides blocking carboxylation of coagulation factors through vitamin K inhibition, warfarin acts on other extrahepatic gamma-carboxyglutamic (Gla) proteins, whose activity is also regulated by vitamin K-dependent carboxylation. These proteins include matrix Gla protein (MGP) and osteocalcin, or bone Gla protein (BGP).…”

“…Impairment of the function of MGP and BGP results in an increased risk for developing vascular calcification and osteoporosis, respectively, which are the possible side effects of warfarin treatment and have been demonstrated in animal experiments and in clinical practice. 3 One way of interpreting the results of the study by Buschbacher et al 2 is that in the short term warfarin treatment could be protective by blocking osteocalcin in the presence of pro-inflammatory factors or in the event of a reduction of calcification inhibitors that would favour the ossification process. However, although the results of the study by Buschbacher et al 2 are intriguing, stronger evidence should be provided for considering warfarin as a potential inhibitor of ossification.…”

What did we learn from new oral anticoagulant treatment?

“…Warfarin leads to vascular calcification, especially of valves [13]. This may contribute to future heart attacks or heart failure.…”