~ Vitamin K's Delicate Balancing Act, Part 2

Critical Role in Vascular Health

Scientists are continuing to learn more about the process by which atherosclerotic arteries become calcified. Calcification is now recognized not merely as an accumulation of calcium similar to build-up inside a pipe, but as an active biological process virtually identical to bone mineralization.40,41 Crucial to both processes, vitamin K produces opposite effects in bone and blood vessels: matrix Gla-proteins in bone increase mineralization when activated by vitamin K, while similar proteins in blood vessel walls decrease vascular calcification.42 Both actions are healthy responses that maintain strong bone and supple blood vessels.

Inflammatory change in the blood vessel wall, and an increase in the size and number of smooth muscle cells, play a major role in atherosclerosis.43,44 Vitamin K-dependent matrix Gla-proteins holding vascular cells and other components together have proven to be vital in preventing calcification following an initial inflammatory injury.45

The simultaneous loss of calcium from bone and deposition of calcium in arteries has been called the “calcification paradox.”37 This double-jeopardy situation occurs frequently in postmenopausal women, apparently in part because of incomplete formation of the crucial Gla-proteins that normally both increase bone calcification and prevent arterial wall calcification.

Scientists are greatly interested in vitamin K’s role as a possible anti-atherosclerosis or anti-calcification agent.30 In an observational study of dietary vitamin K in coronary heart disease, researchers in the Rotterdam Study found that subjects with above-average intake of vitamin K2 had reduced mortality from coronary heart disease, as well as lower all-cause mortality.46 In addition, the likelihood of having severe aortic calcification was lower in subjects with higher K2 intake. The authors suggest that an adequate intake of vitamin K2 could be important in preventing coronary heart disease. Vitamin K intake earlier in life does not seem to be associated with premature coronary calcification, suggesting that vitamin K’s effects on blood vessels become more important with advancing age.47

Deficiencies in Intake and Production

Unlike the other fat-soluble vitamins A, D, and E, which can be stored in body fat, vitamin K has no significant storage pool in the body. Humans can therefore develop a vitamin K deficiency in as few as 7-10 days of a vitamin K-deficient diet, even with functioning intestinal bacteria.9

Despite the fact that older adults typically consume more dietary vitamin K than younger adults,21 elderly people may suffer from low levels of vitamin K. In one study, 12% of patients at an older adult outpatient clinic had very low plasma levels of vitamin K.48

VITAMIN K AND VASCULAR CALCIFICATION

A recent study from the Netherlands provides strong laboratory and clinical support for vitamin K’s role in preventing vascular calcification.45

After staining both healthy and diseased tissue for normal, carboxylated Gla-proteins and for under-carboxylated proteins, researchers found that carboxylated Gla-proteins were located in the healthy middle layer of arteries, while under-carboxylated proteins were present in the cells lining the arteries, where they were associated with microscopic bubbles in the lining. The same researchers then measured carboxylated Gla-protein levels in the blood of patients who had required coronary angioplasty, and found them to be lower than those of healthy people.



Newborn infants represent the largest population that regularly suffers from bleeding due to overt vitamin K deficiency. Because newborns do not have any bacteria in their intestines at birth, for several days they are vulnerable to bleeding until they develop a normal intestinal population. For these reasons, the American Academy of Pediatrics recommends that all newborns receive an intramuscular dose of vitamin K at birth.49 Babies who are exclusively breast fed may require additional doses of vitamin K to support them until they develop healthy intestinal flora.50

A report of two cases of post-operative bleeding in non-infants (a 73-year-old and a 6-year-old) highlights the complex balance of vitamin K supply and demand.51 While normal gut bacteria almost always ensure ample vitamin K to prevent clotting problems, these two patients had undergone long courses of antibiotics that may have destroyed those beneficial bacteria. This internal deficiency state, added to high utilization of vitamin K-dependent pro-coagulant proteins in the post-operative period, was thought to account for the bleeding. When the patients were given vitamin K, coagulation immediately returned to normal. Such cases are mercifully rare, but they serve as additional evidence of the narrow window between vitamin K sufficiency and deficiency states.

The use of broad-spectrum anti-biotics to treat serious infections is known to produce vitamin K deficiency that can be severe enough to cause bleeding.52 Patients who undergo bone marrow transplants are often dependent on vitamin K supplementation, as their intestinal bacteria are intentionally obliterated in preparation for the destruction of their own bone marrow germ-fighting cells.53

Deficiencies in Absorption

Poor absorption of fats is generally a hallmark of liver and gall bladder diseases. Bile acids, produced in the liver and excreted by the gall bladder, function as “detergents” in the small intestine, aiding in the absorption of fats and the fat-soluble vitamins. For these reasons, people with obstructed bile ducts and decreased small intestinal bile acid concentrations almost always develop deficiencies of the fat-soluble vitamins A, D, E, and K.10,12 Fortunately, proper management of diet and vitamin supplementation usually prevents significant vitamin deficiencies in patients with chronic obstructive biliary diseases.13

Consumption of hydrogenated and saturated fats has well-known adverse effects on blood lipid profiles. The hydrogenation of fats produces a hydrogenated form of vitamin K called dihydrophylloquinone, which is not absorbed as well as unsaturated (normal) vitamin K and also appears to be ineffective in promoting bone production.54 These data further support avoiding foods that contain saturated fat and supplementing with vitamin K when a diet high in saturated fat cannot be avoided.

Vitamin K Antagonist Drugs

The most important form of vitamin K “deficiency” in adults is not related to intake or absorption, but rather to the use of vitamin K antagonists such as warfarin (Coumadin®).55,56 Vitamin K antagonists prevent vitamin K from activating Gla-proteins in the coagulation cascade. Warfarin is a commonly used drug among older patients, and has been approved for many conditions requiring short- and long-term anticoagulation.57 Long-term anticoagulation, however, carries certain risks, such as bleeding complications. The likelihood of these complications is greater in patients with preexisting vitamin K deficiency.

It takes several days after beginning warfarin therapy to achieve the desired antithrombotic effect.58 Almost all patients subsequently experience periods of fluctuation in their international normalized ratio (INR), a measure of the blood’s ability to clot properly. This sometimes leads to bleeding or clotting complications. Older patients generally tend to be more sensitive to warfarin’s effects, both near the beginning of treatment when coagulation status may fluctuate widely, and later during maintenance treatment.58 Genetic differences in sensitivity to warfarin account for some of the fluctuations as well. For example, Asian-Americans tend to require much lower doses of warfarin to achieve anticoagulation than do African-Americans.59,60

For people using warfarin, maintaining normal INR values is usually adequate to prevent dangerous clots without posing the risk of serious bleeding. The risk of clinically significant bleeding rises with elevation of INR to levels above the normal range.61

When warfarin causes excessive INR elevation but no active bleeding is evident, doctors may sometimes recommend skipping one or more doses of warfarin, which will slowly restore the INR level back to normal. More rapid, safe reversal can be accomplished with small oral doses of vitamin K1.57 Oral vitamin K at a dose of 1 mg (1000 mcg) daily is effective in treating patients whose INR has become too high, even up to levels that are three times higher than the upper limit of the normal range.62 In a placebo-controlled trial among patients with elevated INR but no symptomatic bleeding, 1 mg of oral vitamin K restored INR to safe therapeutic levels faster than placebo (all patients had their warfarin doses stopped). Patients treated with vitamin K also had fewer episodes of bleeding than control patients.63 This study is one of several that demonstrate the safety and effectiveness of using low-dose vitamin K in patients still on warfarin.64-66 A recent systematic review of the literature concluded that low-dose oral vitamin K is the preferred strategy for rapidly restoring INR levels in patients who were not actively bleeding.61

Fluctuating INRs can also go below the therapeutic range, putting patients at risk for clotting complications, especially when the warfarin dose is held constant.67 In 2005, University of Texas researchers studied eight patients on warfarin treatment whose INRs had been fluctuating.68 All patients were started on daily supplementation with oral vitamin K (100 mcg/day) while their INR responses were monitored. Nearly all patients experienced diminished fluctuations while taking the supplements, with more INRs in the therapeutic range than before treatment. The patients’ total amount of time with INRs within the target range also increased. These results suggest that low-dose vitamin K may help to maintain a small reserve capacity of active coagulation factors that can smooth out the variability in INR caused by warfarin, without creating excessive coagulation.

Other Effects of Vitamin K Antagonists

Supporting active vitamin K-dependent Gla-proteins in patients on warfarin is also a good idea in light of what we have learned about the importance of these proteins in tissues besides blood. Because warfarin inhibits activation of Gla-proteins, it has the potential to reverse vitamin K’s effects, causing reduced calcification of bone and increased calcification of blood vessels. Both laboratory and clinical evidence support this suspicion.42 Warfarin blocked vitamin D-induced production of the bone protein osteocalcin in a laboratory model;69 subsequently, doses of warfarin comparable to those used in humans reduced bone strength and volume in laboratory rats.70 Reduced bone mineral density has been observed in warfarin-treated patients,71 and an association between the chronic use of warfarin and fracture risk has been reported in humans.72,73 A recent study of children on long-term warfarin therapy found significantly lower bone mineral density in the lumbar spine of treated patients than in a group of randomly selected controls.74

TOPICAL VITAMIN K REDUCES BRUISING SEVERITY

Topical application of vitamin K may help speed the healing of bruises, according to a study from the University of Miami School of Medicine.77 Cosmetic procedures such as pulsed dye laser treatment often result in significant bruising. The Miami team investigated whether topical vitamin K could help prevent or clear bruising induced by laser treatment.

Twenty-two patients were enrolled in this randomized, double-blind, placebo-controlled trial. Eleven participants applied vitamin K cream to half of the face and a similar cream containing no vitamin K to the other half of the face for two weeks prior to laser treatment. The other 11 subjects followed the same procedure each day for two weeks following the laser procedure.

The side of the face treated with topical vitamin K prior to laser treatment showed no significant difference in bruising compared to placebo. However, the side of the face treated with vitamin K after treatment demonstrated significantly lower scores of bruising compared to the placebo-treated side.77

While pre-treatment with vitamin K cream does not appear to prevent bruising, application of vitamin K cream following laser treatment may help reduce the severity of bruising, particularly in the initial days of application.77



Arterial calcification, which is prevented by vitamin K-dependent matrix proteins, might also be influenced by warfarin treatment.14 Arterial calcification has been produced experimentally in rats by treatment with warfarin.40,41 In a 2005 study of older patients with known calcification of the aortic valve, those who had been on long-term oral anticoagulation therapy had markedly more calcium in their coronary arteries and aortic valves than did patients who had not been on such treatment.75

Conclusion

In addition to its effects on the coagulation cascade, vitamin K is now known to be involved in many of the body’s most critical functions. Bone mineralization and vascular calcification, two bodily functions affected by aging, are fundamentally related to each other through the actions of vitamin K. It is becoming increasingly clear that vitamin K antagonists (like warfarin) may have the unintended effects of exacerbating osteoporosis and atherosclerosis. Fortunately, the very science that revealed this new threat probably holds the answer to preventing it.

In 2005, a Japanese study demonstrated that the Gla-proteins governing coagulation require higher doses of warfarin for inhibition than do those that control bone mineralization.76 If confirmed, this exciting finding raises the possibility that careful, low-dose vitamin K supplementation could prevent warfarin’s deleterious effects on bone and blood vessel calcification, while preserving its beneficial effect of anticoagulation. University of Texas researchers have already demonstrated the safety and benefit of low-dose vitamin K supplementation in patients taking warfarin.68

NEW APPLICATIONS FOR VITAMIN K

In the last two years, scientists have uncovered several potential applications for vitamin K. Here is a summary of the most recent research demonstrating vitamin K’s wide applicability in human health beyond its well-known role in blood clotting.

  • Cancer-fighting effects. The hepatitis C virus is a leading cause of liver cancer. An 85-year-old man with hepatitis C and advanced liver cancer recently underwent marked regression of his tumor while using vitamin K therapy.78 Laboratory evidence in the last year provides an understanding of the mechanism of this anti-cancer effect.79-82 In 2005, vitamin K was also shown to have anti-leukemia effects.83 These anti-cancer capabilities seem to arise from vitamin K’s power to selectively inhibit cell growth and induce apoptosis (programmed cell death).84 This is an exciting and growing area of cancer therapy.
  • Improving cancer detection. Blood levels of “proteins induced by vitamin K absence or antagonist” (PIVKA) are elevated in liver cancer patients.85 PIVKA is a measure of insufficient vitamin K activity. In 2005, elevated PIVKA levels were correlated with a variety of other cancers.86,87 PIVKA testing may one day serve as a useful and sensitive marker of tumor progression or treatment success. Elevated PIVKA levels also raise the intriguing possibility that vitamin K deficiency could be related to the cause and possibly the treatment of some cancers.
  • Modulating inflammation. The vitamin K-dependent protein C has powerful anti-inflammatory capabilities. Activated protein C has been used in reducing the damage caused by the immune system in advanced bacterial sepsis.24,88
  • Supporting healthy bones. Earlier this year, researchers demonstrated that long-term use of anticoagulants is associated with increased risk of osteoporotic fractures.89 This is an unsurprising finding in light of other work demonstrating a link between anticoagulant drugs and abnormalities in measures of bone calcification.71 In a 2005 study, vitamin K-rich compounds in sweet potato leaves not only stimulated bone formation through vitamin K activity, but also seemed to inhibit bone resorption through the actions of other components.90
  • Protecting vascular health. Very recent work has shown that vitamin K antagonists such as warfarin may promote blood vessel calcification.45,91 Postmenopausal women who supplemented with vitamins D and K had less calcification and superior arterial vessel wall elasticity than placebo-treated subjects.92



Patients taking warfarin (Coumadin®) or other vitamin K antagonists should talk with their doctors about this recent literature, to learn whether regular, low-dose supplements of vitamin K (100 mcg/day), taken under careful medical supervision, may be right for them. Because of the considerable evidence for increasing the daily recommended dose of vitamin K,14,15,17,20 people who are not taking anticoagulant medication may want to consider beginning daily supplements of vitamin K to support the Gla-proteins that can slow osteoporosis and reduce arterial calcification.36 For people in good health, doses of 10 mg to 40 mg have been used.39

References . . .


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