Study Title:

How Coumadin Affects Vitamin K Function

Study Abstract

The triage theory posits that some functions of micronutrients (the 40 essential vitamins, minerals, fatty acids, and amino acids) are restricted during shortage and that functions required for short-term survival take precedence over those that are less essential. Insidious changes accumulate as a consequence of restriction, which increases the risk of diseases of aging. For 16 known vitamin K–dependent (VKD) proteins, we evaluated the relative lethality of 11 known mouse knockout mutants to categorize essentiality. Results indicate that 5 VKD proteins that are required for coagulation had critical functions (knockouts were embryonic lethal), whereas the knockouts of 5 less critical VKD proteins [osteocalcin, matrix Gla protein (Mgp), growth arrest specific protein 6, transforming growth factor β–inducible protein (Tgfbi or βig-h3), and periostin] survived at least through weaning. The VKD -carboxylation of the 5 essential VKD proteins in the liver and the 5 nonessential proteins in nonhepatic tissues sets up a dichotomy that takes advantage of the preferential distribution of dietary vitamin K1 to the liver to preserve coagulation function when vitamin K1 is limiting. Genetic loss of less critical VKD proteins, dietary vitamin K inadequacy, human polymorphisms or mutations, and vitamin K deficiency induced by chronic anticoagulant (warfarin/coumadin) therapy are all linked to age-associated conditions: bone fragility after estrogen loss (osteocalcin) and arterial calcification linked to cardiovascular disease (Mgp). There is increased spontaneous cancer in Tgfbi mouse knockouts, and knockdown of Tgfbi causes mitotic spindle abnormalities. A triage perspective reinforces recommendations of some experts that much of the population and warfarin/coumadin patients may not receive sufficient vitamin K for optimal function of VKD proteins that are important to maintain long-term health.

From press release:

An important analysis conducted by Children's Hospital Oakland Research Institute scientists suggests the importance of ensuring optimal dietary intakes of vitamin K to prevent age-related conditions such as bone fragility, arterial and kidney calcification, cardiovascular disease, and possibly cancer (1). Vitamin K is concentrated in dark green plants such as spinach or Swiss chard, and is either not present or present in only small amounts in most multivitamin pills.

This finding comes from Associate Staff Scientist, Joyce McCann, PhD, and Senior Scientist, Bruce Ames, PhD, who analyzed data from hundreds of published articles dating back to the 1970's. Their review was designed to test Dr. Ames' "triage" theory that provides a new basis for determining the optimum intake of individual vitamins and minerals (also called micronutrients), and has major implications for preventive medicine. The analysis, which strongly supports his theory, will be published in the October 2009 issue of the American Journal of Clinical Nutrition.

Dr. Ames proposed the triage theory in 2006 (2) to explain numerous observations from his own lab and the scientific literature. The theory explains why diseases associated with aging like cancer, heart disease, and dementia (and the pace of aging itself) may be unintended consequences of mechanisms developed during evolution to protect against episodic vitamin/mineral shortages. If correct, the triage theory has widespread implications for public health because modest vitamin/mineral deficiencies are quite common. The theory also suggests a new scientifically based and consistent strategy for establishing optimal vitamin/mineral intake standards, and it provides a research strategy to uncover early biomarkers of chronic disease.

Vitamin K is known as the "Koagulation" vitamin because about half of the 16 known proteins that depend on vitK are necessary for blood coagulation. The other vitK-dependent proteins are involved in a variety of different functions involving the skeletal, arterial, and immune systems.

Average intakes of vitamin K in the United States and the United Kingdom are less even than currently recommended intakes, which are primarily based on levels to ensure adequate coagulation. McCann & Ames' analysis supports recommendations by some experts that non-clotting functions requiring vitamin K may need higher intakes than are currently recommended.

McCann says, "Encouraging support for the triage theory from our vitamin K analysis suggests that experts aiming to set micronutrient intake recommendations for optimal function and scientists seeking mechanistic triggers leading to diseases of aging may find it productive to focus on micronutrient-dependent functions that have escaped evolutionary protection from deficiency."

This vitamin K analysis is the first in a series of literature-based studies conducted by Drs. Joyce McCann and Ames to test the basic premises of the triage theory. As a reviewer of the manuscript notes, "…this review provides a unique perspective of consequences of vitamin K insufficiency and may serve as an important future reference, as new vitamin K dependent proteins are identified and new (non-clotting) functions of vitamin K are elucidated. More broadly, an assessment of micronutrient sufficiency from the perspective of triage theory may provide a valuable point of view, as current recommendations for nutrient intakes are reconsidered."

Study Information

Joyce C McCann and Bruce N Ames
Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging.
American Journal of Clinical Nutrition
2009 October
Children's Hospital Oakland Research Institute, Oakland, CA.

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