Update: Nattokinase and Vitamin K2 (MK 7)

This update was prompted by a post by Dean and response by Hans a while back. It took me quite some time to make contact with Dr. Holsworth and then Thanksgiving arrived and the project was set aside again. My apologies for the delay. Refer to: <[www.afibbers.org]>

Since my original Conference Room Nattokinase posts 39 and 40 and other updates, Dr. Holsworth has provided more insight and information from new studies and with this post, I hope to help clear up the confusion.

While these are two different nutrients, they are somewhat interrelated when we discuss them, so it seems appropriate to address both.

I’ll start with a short piece on nattokinase and then concentrate on the vitamin K2 discussion because while vitamin K2 (MK7) dosing must be supervised for those on warfarin/Coumadin, the use of this important vitamin is very exciting and encouraging to help prevent soft tissue calcifications, prevent osteoporosis and actually reverse arterial calcifications in everyone. It can even be used by those on anti-coagulant therapy when supervised by a physician. This is huge for people who must use warfarin because of prosthetic heart valves.

Studies indicate that long-term warfarin/Coumadin use contributes to soft tissue calcifications as well as osteoporosis, so this is both important and encouraging news for everyone who takes this blood-thinning drug.

But, it’s important to know and understand the difference in vitamers or isomers of K as it is the form of K2 (MK7) and not vitamin K1 that is involved in this benefit.

Jackie

Part I

Be aware of the names. The enzyme is nattokinase; the cheese curd or food is called natto. Do not slip into the habit of substituting one name for the other or confusion reigns.

Nattokinase
It seems that as more people have been using the enzyme nattokinase (NK), the comfort level in recommending adjuncts along with it have become acceptable. Initially, recommendations were conservative. Remember the enzyme used must be of the NSK-SD designation which is an assayed form to ensure purity from any residual vitamin K from the manufacturing process.

Nattokinase & aspirin
Since they don’t work on the same clotting mechanism… aspirin being anti-platelet and the enzyme, nattokinase, working on fibrinogen levels to lower blood viscosity, both can be used together. Just be aware of the minor risk potential for nosebleeds as a sign of too much aspirin.

Natto food & warfarin/Coumadin
The only time an afibber needs to be concerned about using natto food is if they are on warfarin/Coumadin. This is because of the higher vitamin K2 content in the form Menaquinone 7 (MK7) that is predominant in natto food. In natto food, the amount of MK7 is not regulated, measured or standardized for consistent quantity. Since MK 7 has a long half life, 3 days,(meaning it stays in the body and will be cumulative if eaten daily), it would exceed the maximum limit of not over 100 mcg. K2 (MK 7) safe to use along with warfarin.

Dean states his 50 gram serving yields an approximate equivalency of MK 7 as 387 micrograms.

You’ll see from the explanation that follows, this amount, in one dose for a person using Coumadin, would be far over the 50-100mcg range where warfarin interference is detected. Further, to use it daily - since MK 7 is cumulative due to long half-life - would be a high risk for anyone on Coumadin or similar anti-coagulants to consume the natto food. This is not a problem for others.

In the foregoing referenced forum post, Hans points out that the study cited used 45 mg. MK 4 which is not the same as MK 7 as you’ll note from the information that follows.

I asked Dr. Holsworth about the studies and he commented that vitamin K researcher, Dr. Vermeer is not convinced that MK-4 is very useful at all because of the small Japanese trials, short half-life, limited extrahepatic function and huge doses required.

Part 2

Vitamin K 2

The confusion typically lies in the designations of K, K1, K2, MK4, MK7 even among supplement manufacturers in identification of the vitamin K derivative or isomer form they use in products. Hopefully this will serve to clarify.

There is abundant literature explaining the various forms of vitamin K, K1, 2, and K3 (synthetic and not useful). The classic publication comes from M J Shearer, published in Lancet, Vol 345, January 28, 1995.

Vitamin K1 is phylloquinone aka phytonadione and the highest content is found in leafy green vegetables such as lettuce, broccoli, spinach kale and makes up about 90% of our vitamin K intake in a typical Western diet. The absorption of vitamin K1 from vegetables is only about 10%. Some K1 is converted to MK 4.

[u/] Vitamin K2[/u] has two major vitamers, Menatetrenone (MK-4) and Menaquinone 7 (MK7) which have a more restricted distribution in the diet than phylloquinone, with nutritionally significant amounts of MK-4 only occurring in animal meat and liver and higher menaquinones (MK 7) through MK9) occurring in fermented products produced by bacteria like natto, cheese and cheese curd. Menaquinones make up the other 10% of vitamin K intake and can be synthesized in the gut by microflora and also made from K1

An important distinction, MK 4 appears to be synthesized by animals (including humans) from phylloquinone. MK 4 is found in a number of organs other than the liver at high concentrations than phylloquinone. However, MK4 has a very short half-life time (about 1 hour) whereas MK7 has the much longer half-life of 72 hours and reaches a steady tissue level after about two weeks of dosing.

This would explain why the study referenced by Hans used large doses of MK4 (1 and 45 mg/day) because it is much more difficult to maintain constant levels.

Only 3-8 % of phylloquinone (K1) is absorbed and then is horded by the liver. Menaquinone-7 is greater than 90% absorbed and since it is lipophilic, it is carried by lactate dehydrogenase (LDH) from the liver to the systemic circulation providing MK-7 to the arteries and bones.

Current research concludes that the MK 7 form of K2 is the most effective for the therapeutic intention of reducing and preventing soft tissue calcification and/or osteoporosis. It is important to emphasize that it is vitamin K2 or MK 7 and not vitamin K1 that is involved in this therapeutic benefit.

In some products and studies the Vitamin K2 is MK-4 which is a shorter chain and is not absorbed as well. MK-4 does not work outside the liver because it is less lipophilic than MK-7 (menaquinone-7). MK-4 is also animal-derived (liver) where MK-7 is derived from natto and is non-GMO.

Supplemental forms of both K1 and K2 are well absorbed as long as they are taken with some dietary fat to stimulate bile secretion.

Once again….vitamin K2 – mainly - as MK 7 but also MK 4 has benefit with two important roles –

It helps keep calcium out of soft tissues such as blood vessels and aorta (preventing calcification deposits), bone spurs and also with the help of vitamin D3, directs calcium into bones to reduce risk of osteoporosis. This is especially important for those using warfarin/Coumadin whether or not they are afibbers.

Earlier studies indicated benefits from MK4 but later studies confirm that MK 7 is actually the most beneficial.

Both forms or vitamers of vitamin K can safely taken together.

The rest of this discussion references only MK 7


We sometimes worry about getting too much vitamin K since it is involved in the clotting mechanism and this is of special interest to all afibbers but especially those using warfarin/Coumadin.

Important Note
Supplemental vitamin K 2 in the form of MK 7 can be used with warfarin when physician directed so INR levels can be closely monitored as interference with warfarin by (K2) MK 7 is seen in doses ranging from over 50 to 100 micrograms (mcg).

Aspirin (ASA) is an anti-platelet aggregation inhibitor and not a Vitamin K antagonist so MK-7 and ASA are very compatible for those not using an anticoagulant.

Vitamin K2 as Menaquinone or MK 7

I note that many are labeling K2 as the active ingredient and then listing anywhere from 1 – 45 milligrams per capsule/dose. This is misleading and needs clarification as they are generalizing the K2 term and not specifying that it is really menaquinone 4 and not MK7 – which is the one studies find to be most effective.

[/u]The Value of Supplemental Vitamin K 2 – MK 7[/u]

The liver is the place of clotting factor synthesis and utilizes dietary vitamin K very efficiently for that reason. It is questioned if the RDA for vitamin K is adequate to cover the requirements outside the liver.

It has been suggested that perhaps all or most all of apparently healthy adults are subclinically vitamin K deficient based on the findings that increased circulating levels of undercarboxylated osteocalcin were shown to be associated with bone loss and osteoporosis in post menopausal women and undercarboxylated MGP is associated with arterial calcification.

It helps to point out that the liver requires so much vitamin K, it can leave the cartilage and bone CGCA (the amino acid gamma carboxyglutamic acid) proteins with inadequate levels so the vitamin K requirements for the cardiovascular system and cartilage (for bone production) may not be met even though normal clotting factor production occurs because this goes on in the liver (and the liver gets first call on vitamin K utilization.)

The body can store about one month supply of vitamin K. Antibiotics interfere with intestinal bacterial production of vitamin K.


[At the end of this report, I’m listing several other observations currently being studied linking vitamin K deficiency with chronic degenerative disease conditions. Be sure to read through to the end.]


Studies indicate that K2 (MK 7) is superior to K1 for vascular health, carotid artery elasticity, and maintenance of bone strength and since it has the long half-life and bypasses the liver is thought to be the obvious choice for enrichment of dietary supplements and functional foods used for disease prevention in healthy subjects.

Reference:
Vitamin K: The coagulation vitamin that became omnipotent Cranenburg EC, Schurgers LJ, Vermeer C. Thromb. Haemost. 2007 Jul;98(1):120-5.
[groups.google.com] (I have the full text – email me for the file)

Unless one is on warfarin/Coumadin, there is no reason to limit intake of vitamin K2 in the form of MK 7.

Good news about arterial calcification caused by anti-coagulant (warfarin) therapy. Studies show that use of Vitamin K2/MK 7 – in supervised doses by a physician, can eliminate the risk of not only the calcification of soft tissue but also the risk of osteoporosis that also accompanies anti-coagulant therapy. MK-7 has demonstrated its ability to support de-arterial calcification and increase arterial compliance by 50%.

Dr. Holsworth works with physicians to instruct them on safe dosing and monitoring of the INR stability. The NZymeCeutical product he supplies called – MK2 - is the purified form and is assayed twice before sending to the patient – the same as with their Nattokinase product.

The MK-7 product is contentrated so 1 mg of powder = 1 microgram of MK-7.

You can order NZyme MK7from NZymeCeuticals
Phone 877-460-1600.
NZyme MK-7 pharmaceutical-grade capsule contains 100 mcg (micrograms) of pure active menaquinone-7 and are exclusively non-GMO (non-genetic mutant organisms).
Call for current pricing. The last order I received was $12 for 30 capsules plus shipping.

Visit [www.nzymeceuticals.com] to check out the homepage and links and note some of the articles offered on Dr. Holsworth’s blog.

I urge you to read the following referenced studies and then share them with your physician if you are on warfarin. When you see the names Shearer, Schurgers or Vermeer regarding vitamin K research, know that these are the foremost experts. Dr. Holsworth collaborates with them for his product research.

If you can’t access these online, then just email me and I’ll send to you from my computer files.

References

Vitamin K: The coagulation vitamin that became omnipotent
Thromb. Haemost. 2007 Jul;98(1):120-5. Cranenburg EC, Schurgers LJ, Vermeer C.
Department of Biochemistry,
University of Maastricht, P.O. Box 616, 6200 MD
Maastricht, The Netherlands. E-mail: c.verm...@bioch.unimaas.nl.

Vitamin K, discovered in the 1930s, functions as cofactor
for the posttranslational carboxylation of glutamate
residues. Gammacarboxy glutamic acid (Gla)-residues were
first identified in prothrombin and coagulation factors in
the 1970s; subsequently, extra-hepatic Gla proteins were
described, including osteocalcin and matrix Gla protein (MGP).
Impairment of the function of osteocalcin and MGP due to
incomplete carboxylation results in an increased risk for
developing osteoporosis and vascular calcification, respectively,
and is an unexpected side effect of treatment with oral
anticoagulants.

It is conceivable that other side effects, possible involving
growth-arrest-specific gene 6 (Gas6) protein will be
identified in forthcoming years. In healthy individuals,
substantial fractions of osteocalcin and MGP circulate
as incompletely carboxylated species, indicating that the
majority of these individuals is subclinically vitamin
K-deficient.

Potential new application areas for vitamin K
are therefore its use in dietary supplements and functional
foods for healthy individuals to prevent bone and vascular
disease, as well as for patients on oral anticoagulant
treatment to offer them protection against coumarin-induced side
effects and to reduce diet-induced fluctuations in their INR values.
PMID: 17598002 [PubMed - in process]
Related Links
Role of vitamin K and vitamin K-dependent proteins in vascular calcification. [Z Kardiol. 2001] PMID:11374034
Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. [J Biol Chem. 1985] PMID:3877721
Adverse effects of coumarin anticoagulants. [Drug Saf. 1993] PMID:8260120
Effects of vitamin K on bone mass and bone metabolism. [J Nutr. 1996] PMID:8642454
Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. [Arterioscler Thromb Vasc Biol. 2005] PMID:15961706

Is vitamin K deficiency more common than thought?
[www.nutraingredients.com]


"Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats"10.1182/blood-2006-07-035345
[bloodjournal.hematologylibrary.org]

Vitamin K may reverse arterial calcification
Article by Stephen Daniels 3/04/07
[www.nutraingredients-usa.com]

Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency.
Osteoporos Int. 2001 Dec;12(12):996-1000
[www.ncbi.nlm.nih.gov]

Vitamin K2 higher bioavailability than K1, say scientists
[www.nzymeceuticals.com]

Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7
Blood. 2006 Dec 7 - Schurgers LJ, - Teunissen KJ, - Hamulyak K, - Knapen MH, - Vik H, - Vermeer C. VitaK & Cardiovascular Research Institute CARIM, University of Maastricht, Maastricht, Netherlands.

Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone) and matrix Gla-protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health relatively high intakes of vitamin K are required. The synthetic short chain vitamin K1 is commonly used in food supplements, but recently also the natural, long chain menaquinone-7 (MK-7) has become available as an OTC supplement.

The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K1 and MK-7. Serum vitamin K species were used as a marker for absorption, and osteocalcin carboxylation as a marker for activity. Both K1 and MK-7 were absorbed well with peak serum concentrations at 4 h after intake.

A major difference between both vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels and accumulation of MK-7 to higher levels (7-8 fold) during prolonged intake.

MK-7 induced more complete carboxylation of osteocalcin and hematologists should be aware that preparations supplying >/=50 microg/day of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.

PMID: 17158229 [PubMed - as supplied by publisher]
[www.ncbi.nlm.nih.gov]

Intake of Fermented Soybeans, Natto, Is Associated with Reduced Bone Loss in Postmenopausal Women: Japanese Population-Based Osteoporosis (JPOS) Study
Yukihiro Ikeda*,2, Masayuki Iki*, Akemi Morita*, Etsuko Kajita, Sadanobu Kagamimori**, Yoshiko Kagawa and Hideo Yoneshima Nutritional Epidemiology 2006 American Society for Nutrition J. Nutr. 136:1323-1328, May 2006 [jn.nutrition.org]

Nattokinase references

I have a pdf file of an article published in The American Journal of Health-System Pharmacy Alternative Therapies “Nattokinase for prevention of thrombosis” which I will forward if you send me an email and request it.
Nattokinase for prevention of thrombosis
Tai and Sweet Am J Health Syst Pharm.2006; 63: 1121-1123

Nattokinase- The Blood Desludger
by Ralph O. Holsworth, Jr. D.O.

[www.nzymeceuticals.com]
[www.naturalproductsinsider.com]

More on Vitamin K2

Anti-inflammatory actions shown in research indicate as the body ages, increased levels of the inflammation-promoting cytokine Interleukin 6 (IL 6) occur. When IL-6 becomes out of balance with the other cytokines, inflammation accelerates. Research notes that in people with arthritis, Alzheimer’s, and atherosclerosis have higher levels of IL-6. A study by National Research Institute in Italy found that subjects with the highest levels of IL-6 were almost twice as likely to develop mobility related disabilities.

Diabetes developed in test animals when vitamin K deficiency was induced in a Japanese study. The pancreas has the second highest concentration of vitamin K in the body and plays the major role in blood glucose and insulin regulation.

Antioxidant – research indicates vitamin K has antioxidant activity comparable to vitamin E and CoQ10.

Alzheimer’s About 25% of the population have a genetic predisposition for developing Alzheimer’s disease if they carry the E4 form of the lipoprotein apoE. People with this gene also have been found to be low in vitamin K. Since calcification and development of lesions in blood vessels supplying the brain are believed to be a component of Alzheimer’s development, it would be good to investigate high-dose vitamin K therapy as a preventive measure.

Liver Cirrhosis –related liver cancer
Japanese research indicated vitamin K2 may be preventive of liver cancer caused by viral cirrhosis. There is a 2004 JAMA study discussing 40 women treated with 45 mg. vitamin K2 per day. It was found to decrease the risk of development possibly by delaying the onset. The women were followed for over 7 years and the women who did develop liver cancer was significantly smaller in the vitamin K2 group. It is thought that a substance called geranyl-geraniol which is a by-product of K2 induces cell death in tumor cells and may be important in cell growth inhibition. A research note indicated “…..vitamin K2 decreases the risk of liver cancer to about 20% compared to the control group.” This was just a preliminary report at that time back in 2004.

(JAMA, 2004 July 21:292(3)358-61 Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver.

Reference:
Focus 2005 – “Vitamin K2 Putting Calcium Where it Belongs”
Allergy Research Group publication.
I have a reference list for these benefits. You can email me for them.


Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin,"
Blood First Edition Paper, prepublished online November 16, 2006; DOI 10.1182/blood-2006-09-049262.

Vitamin K in High Doses May Reverse Arterial Calcification and Decreased Arterial Distensibility

Reference: "Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats," Schurgers LJ, Spronk HM, et al, Blood, 2006 Nov 30; [Epub ahead of print]. (Address: Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands).

Jackie,
Source Naturals puts out a product it labels "Vitamin K2". The ingredients are listed as:

Vitamin D (as cholecalciferol) 400 IU
Vitamin K (as menaquinone-7) 100 mcg
Calcium 77 mg
Bacillus subtilis Natto Extract 100 mg

Other ingredients: dibasic calcium phosphate, stearic acid, colloidal silicon dioxide, modified cellulose gum, and magnesium stearate.

What do you make of this product? What exactly is the Natto Extract here and what would its effect be on people taking Warfarin?

Thanks for the invaluable info.

Trent

Trent - I would be taking the K2/MK7, D3 and nattokinase - each one separately and by so doing, I would also avoid the fillers I note in this product.

The dose of the D3 is so low it's not worth talking about and I'd just feel comfortable with the known purity of NZymeCeuticals products for these other two important additions.

I note they do not identify the "natto extract" as the NSK-SD enzyme in at least on one of the labels I found online. The natto extract... I presume is nattokinase, although without the NSK-SD designation, we have no way of knowing if it is purified of vitamin K2 or not...so as you point out... if someone on warfarin took this, they could get more MK7 than they should.

They do place a warning to discuss with physician, but if I were on warfarin I would be having my physican work with Dr. Holsworth to be sure of the dosing and the purity and not trust to luck this product.

I am not an employee of NZymeCeuticals and have no financial interests with this company. Dr. Holsworth has been kind enough to work with me in sharing his time to provide educational information on nattokinase and vitamin K2/MK7 and he has generously offered a substantial discount to afibbers of this forum. All you have to do is mention you are an afibber or my name.

As a comparison, I note that Dr. Mercola offers a K2 product for $40 for 30 capsules.

Not to beat this into the ground, but early on when I was researching nattokinase and I attended the Anti-Aging Convention in Las Vegas back in '04, and I met with several suppliers of nattokinase who told me about the pitfalls of finding a pure product and also one that would deliver what was labeled in terms of fibrinolytic units (FUs). There are only a few brands that provide the NSK-SD patented designation and who also assay their batches to ensure that what is labeled is actually delivered in the capsule. Many have been tested and fall very short.

We have explored the feasibility of publishing a list of recommended brands but for the obvious reasons of liability, it is not good business practice and it would require constant monitoring of other brands by assay. That would be expensive and a full time job as batches can vary with every production.

Therefore, either choose the nattokinase brands listing the NSK-SD designation and hope they are honest and not diluting the content
or buy from NZymeCeuticals since they assay every batch twice and we know they do not use GMO products. Most soy is GMO so this is a fairly significant consideration.

Thanks for your input.

Regards,

Jackie

Hi Jackie--

What an impressive piece of work, I am so grateful for all the time and energy you give to all of us.

I am still trying to digest what you have written, and am anxious to add to my supplement regime, but am still on Coumadin, maybe (fingers crossed) only for another few weeks. If this is not the case, I have printed your article and will take it to my EP.

Louise

Jackie,
I was told by my general physician that I should not worry about a high blood fibrinogen level since I am already on Coumadin for a mech aortic valve.
However I also have aortic and coronary calcification and wondering whether the MK7 Vit K would still be an appropriate supplement?
I do selfmonitor my INR/PT and adjust my coumadin dosages to maintain the recommended INR range.
Your valuable comments would be appreciated
Thanks,
Chris

G'day Jackie,
What an amazing piece of research. We are all extremely grateful for your time and diligence and to Dr Holsworth’s research. This has cleared up many issues for me regarding Vit K2. I have only briefly scanned your post so will comment when I have fully studied it.
At the moment I am relief General Manager for the company I work for so maximum stress and adrenaline but the ticker is holding great. So long as I eat the natto food at least 5 times a week I am fine. Anything less see’s the ectopics return. Can you believe it will be 3 yrs in March since I started eating that natto muck?
After nearly 3 yrs natto food still tastes like dog #%$& !

Thanks again.
Dean

People interested in using vitamin K2 when taking Coumadin might want to read the section on Arterial Calcification in the article Living with Warfarin in the Sept 2006 issue of the AFIB Report. Here is a brief excerpt:

"Considering the above findings it is tempting to conclude that daily supplementation with menaquinone (vitamin
K2) would be highly beneficial in reducing arterial calcification (whether warfarin-induced or not), CHD, and
overall mortality without impacting on warfarin’s role in reducing the level of coagulation factors. In other words,
supplementing with moderate amounts of vitamin K2 should not affect INR levels. Clinical trials, of course,
should and hopefully will be carried out to substantiate or negate this hypothesis."

In Hans' recommendations for supplememts to take while on Warfarin, he suggests 100 mcg K2 but emphasizes that INR should be measured while doing so.

Jackie's report covers K2 in more detail, while Hans' article is focused on the effects of warfarin and how to deal with them.

-- Dick

Jackie,

Thank you so much for this excellent piece of research. I have added your posting to session 40 in the Conference Room so as to preserve it for posterity.

Hans

Hi Chris - nice to see you posting.

As the study indicates, supervised by a doctor, it is appropriate to take the MK7 form of vitamin K2 and for you to deal with the calcifications.

I would only trust the NZymeCeuticals brand to be pure so the dose is reliable. You should email him and ask for advice since you are monitoring yourself.

Good luck. Hope you are feeling okay.

Regards,

Jackie

Hi Dean - You are my hero - eating all that natto. I remember well and can't believe that much time has passed.

It were easily obtainable here, I'd be trying it just so I could commiserate with you on the taste. It certainly has me curious.

As you have always maintained, I believe your success with natto food lies with the effect the bacteria have on your GI tract. Whatever works is great.

Best regards,

Jackie

Hans~ Thanks - that's great to have it all in once place.

Best regards,

Jackie