VITAMIN K TOXICITY

[Doogles31731]

There seems to be a general belief within  the Health industries that doses of the vitamin Ks in excess of  physiological requirements, will cause or facilitate emboli of the lungs, heart or other tissues.

I’ve been unsuccessful in finding any evidence to support this, yet it is the basis of the worldwide use of warfarin as an anticoagulant.

I’m looking for solid evidence that excessive vitamin K causes problems, with the emphasis on excessive. Please don’t supply references to the normal role of vitamin Ks in blood clotting.

 If you do find such a reference, would you please highlight the excerpts that support that belief. I would like to scrutinise such evidence, but so far, I have been unable to locate any.

Thank you in advance.

[exchemist]

1 hour ago, Doogles31731 said:

There seems to be a general belief within  the Health industries that doses of the vitamin Ks in excess of  physiological requirements, will cause or facilitate emboli of the lungs, heart or other tissues.

I’ve been unsuccessful in finding any evidence to support this, yet it is the basis of the worldwide use of warfarin as an anticoagulant.

I’m looking for solid evidence that excessive vitamin K causes problems, with the emphasis on excessive. Please don’t supply references to the normal role of vitamin Ks in blood clotting.

 If you do find such a reference, would you please highlight the excerpts that support that belief. I would like to scrutinise such evidence, but so far, I have been unable to locate any.

Thank you in advance.

First of all, what evidence do you have for your claim that the reasons for the use of warfarin as an anticoagulant are to do with excess Vitamin K?

I'm on an anticoagulant myself - though not warfarin - because I am susceptible to atrial fibrillation, which apparently can lead to strokes, that's all.  Vitamin K doesn't come into it.  

[Sensei]

Quote

XYZ toxicity

"The difference between a drug and a poison is the dose"

https://en.wikipedia.org/wiki/The_dose_makes_the_poison

 

[Doogles31731]

exchemist -- I thought it was general knowledge now that warfarin prevents vitamin K from activating blood clotting factors in the liver and that people on warfarin were advised not to take vitamin K supplements in excess of physiological requirements. It has been used for decades as a routine after major surgeries. My problem is that I cannot find any basic literature associating vitamin K supplementation with the formation of emboli.

Sensei -- What you've referenced probably applies to most substances. Can you find any evidence for toxicity of oral vitamin K1 or K2 to any animal or human being? I emphasize oral vitamin K1 or K2, because I know there were some problems with a synthetic vitamin K3 (menadione) and there were some allergies to the base used in some injectibles.

[exchemist]

26 minutes ago, Doogles31731 said:

exchemist -- I thought it was general knowledge now that warfarin prevents vitamin K from activating blood clotting factors in the liver and that people on warfarin were advised not to take vitamin K supplements in excess of physiological requirements. It has been used for decades as a routine after major surgeries. My problem is that I cannot find any basic literature associating vitamin K supplementation with the formation of emboli.

 

I asked you for evidence for your assertion that anticoagulants are widely prescribed in order to counter excess Vitamin K. I think this is completely wrong, you see, so I'd like to understand where you got this idea from so that we can get to the bottom of it. 

What you are now saying is something entirely different, viz. that people on warfarin may be advised not to take Vitamin K supplements.

I trust that you can see the difference between the two. If you can't then evidently we need to discuss it further.  

Edited March 1, 2022 by exchemist

[Doogles31731]

I used  the term 'in excess of physiological requirements". But I'm happy enough to say that people on warfarin are advised not to take vitamin K supplements. It seems self-evident to me that warfarin is used to suppress the activation of blood clotting by vitamin K. I assume that this would be to reduce the chances of emboli or deep vein thrombosis, the belief being that the presence of vitamin K is a contributor to both. And obviously that amounts in excess of physiological doses would be ill-advised.

But I cannot find any evidence in the literature supporting this contention. Hence I'm checking whether I'm missing something that others may know about. 

[Prometheus]

The dosing schedule of warfarin is infamously tricky, requiring regular monitoring to ensure levels remain therapeutic without becoming toxic. As you note, warfarin is a vitamin k antagonist: thus the dose of warfarin is only one side of this equation - dietary intake is the other. For this reason it is usually recommended that people remain on a consistent diet, and the warfarin dose adjusted around this. But sometimes it's easier to recommend for people to manage by simply avoiding certain foods rich in vitamin k.

As for evidence: i imagine you are using google, which will give plenty of results aimed at lay people. If you want the actual evidence base use something like google scholar. Here are the first two papers I came across on scholar: i've only read their abstracts, i share them as an example of what you can find now you know where to look rather than anything definitive.

https://www.tandfonline.com/doi/full/10.1517/14740338.5.3.433?casa_token=G5_umicM8lsAAAAA%3AS4YanznlhhCWxtZrpraK0rxWPT9QyW5EF47eMO3JfpeKte2eekWsfSNqi6EZuxaSASqA41yrwd8

https://www.futuremedicine.com/doi/full/10.2217/pgs.11.184

[exchemist]

29 minutes ago, Doogles31731 said:

I used  the term 'in excess of physiological requirements". But I'm happy enough to say that people on warfarin are advised not to take vitamin K supplements. It seems self-evident to me that warfarin is used to suppress the activation of blood clotting by vitamin K. I assume that this would be to reduce the chances of emboli or deep vein thrombosis, the belief being that the presence of vitamin K is a contributor to both. And obviously that amounts in excess of physiological doses would be ill-advised.

But I cannot find any evidence in the literature supporting this contention. Hence I'm checking whether I'm missing something that others may know about. 

It is well-known that Vitamin K plays a role in blood clotting, in that if you have a deficiency then you may find your blood does not clot properly:   https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-k/

The interaction between Vitamin K and warfarin is explained here: https://www.ihtc.org/warfarin-and-vitamin-k

I am also aware that warfarin is one of the trickier anticoagulants to use, as the dose has to be carefully adjusted for each patient by monitoring its effect.

So it is not altogether surprising that altering vitamin K levels by the use of supplements is not a good idea if you are on warfarin.  

 

P.S. But see also the more technical reply from @Prometheus which came in while I was writing the above. 

 

Edited March 1, 2022 by exchemist

[Doogles31731]

Prometheus and exchemist, I thank you both for your references. I'm familiar with all of that work and I have no problems with it.

I may not be expressing myself properly. So I'll have another go.

For anybody to use a vitamin K antagonist (warfarin) in order to prevent post surgical emboli or deep vein thrombosis, there has to be an assumption that vitamin K is intimately involved in the process of these conditions. At this stage, it appears to be an assumption only, based on the knowledge that vitamin K activates a number of proteins involved in the blood clotting process.

I'm searching to see if anyone has conducted an experiment of any kind to see if they can reproduce emboli or deep vein thrombosis in any animal with higher than physiological doses of vitamin K1 or K2 under any circumstances, with or without surgery in any species. 

And so far it seems safe to say that no such study has been conducted.

I've researched a few studies on the post-operative use of warfarin. RCTs using warfarin vs untreated controls are rare. A couple indicate that there is no significant statistical difference in the number of deep vein thromboses. Maybe I have missed a very good RCT somewhere.

I'll have another look tomorrow. Off to bed now.

 

 

[Prometheus]

2 minutes ago, Doogles31731 said:

For anybody to use a vitamin K antagonist (warfarin) in order to prevent post surgical emboli or deep vein thrombosis,

People will not take warfarin for post-surgical emboli prophylaxis, a low-molecular-weight heparin would be used instead. If people were on warfarin pre-surgery they would be taken off it and reintroduced post-surgery. I'd be interested to see those RCTs that compare post-op use of warfarin vs untreated controls that you found. 

Where are you searching, what keywords are you using?

[exchemist]

2 hours ago, Doogles31731 said:

Prometheus and exchemist, I thank you both for your references. I'm familiar with all of that work and I have no problems with it.

I may not be expressing myself properly. So I'll have another go.

For anybody to use a vitamin K antagonist (warfarin) in order to prevent post surgical emboli or deep vein thrombosis, there has to be an assumption that vitamin K is intimately involved in the process of these conditions. At this stage, it appears to be an assumption only, based on the knowledge that vitamin K activates a number of proteins involved in the blood clotting process.

I'm searching to see if anyone has conducted an experiment of any kind to see if they can reproduce emboli or deep vein thrombosis in any animal with higher than physiological doses of vitamin K1 or K2 under any circumstances, with or without surgery in any species. 

And so far it seems safe to say that no such study has been conducted.

I've researched a few studies on the post-operative use of warfarin. RCTs using warfarin vs untreated controls are rare. A couple indicate that there is no significant statistical difference in the number of deep vein thromboses. Maybe I have missed a very good RCT somewhere.

I'll have another look tomorrow. Off to bed now.

 

 

Try this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911546/

I quote: "The effect of gross changes in vitamin K intake on anticoagulation is a classic. Since the early years of warfarin use myriad case reports and case series have described decreased anticoagulant response due to sudden excessive vitamin K intake. The causes were usually vitamin K rich, vegetable-based, weight reducing diets and food supplements or multivitamins. The culprit amounts of vitamin K consumed ranged from 25 to 6000 µg day⁻¹, but other causes for therapeutic failures were not always excluded [28–31]. Excessive anticoagulation has also been described after unrecorded dietary modification or discontinuation of multivitamin use [31, 32]. 

Suggest following up these references if you are interested.

But I would observe you did this with climate change as well. You jumped to the conclusion that the findings were an "assumption" and that some crucial piece of experimental work had not been done, when the problem was your own lack of understanding of the relevant science background. I suggest you would do better to ask your questions before you start drawing conclusions that there is something wrong with the science.

Edited March 1, 2022 by exchemist

[Doogles31731]

Prometheus, I will put together an answer for you today, but it may take some time and thought.

exchemist, I thank you for that reference, and thank you for posting an excerpt of the relevant paragraphs. It appears to be the type of article I was seeking. I will go through it today. The key to whether it answers my OP question or not, lies in what represents 'therapeutic failure'.

Whilst I very much appreciate your assistance, I do not appreciate your closing condescending comments. I find that I am very curious by nature and I keep asking myself questions about everything I read. My OP was intended as a means of checking that I had not overlooked something before I drew a conclusion. You are very good as a 'helper', but please don't become a 'knocker'. It detracts from your obvious skill as a locator of references.  

[exchemist]

1 hour ago, Doogles31731 said:

Prometheus, I will put together an answer for you today, but it may take some time and thought.

exchemist, I thank you for that reference, and thank you for posting an excerpt of the relevant paragraphs. It appears to be the type of article I was seeking. I will go through it today. The key to whether it answers my OP question or not, lies in what represents 'therapeutic failure'.

Whilst I very much appreciate your assistance, I do not appreciate your closing condescending comments. I find that I am very curious by nature and I keep asking myself questions about everything I read. My OP was intended as a means of checking that I had not overlooked something before I drew a conclusion. You are very good as a 'helper', but please don't become a 'knocker'. It detracts from your obvious skill as a locator of references.  

Then why present a conclusion, effectively accusing the science of being slipshod, before you have gathered the evidence? That is bound to invite criticism.  

[Doogles31731]

15 hours ago, Prometheus said:

People will not take warfarin for post-surgical emboli prophylaxis, a low-molecular-weight heparin would be used instead. If people were on warfarin pre-surgery they would be taken off it and reintroduced post-surgery. I'd be interested to see those RCTs that compare post-op use of warfarin vs untreated controls that you found. 

Where are you searching, what keywords are you using?

Prometheus, I used Google Scholar with the keywords  WARFARIN VS CONTROLS AFTER JOINT SURGERY. I used ANY TIME.

You can see that there are few studies comparing warfarin with untreated controls, and there are some doubts about the dose rates of warfarin used in them

In addition to the following, two of the other early references showed no significant difference between warfarin and controls when 1 mg per day was used as a fixed dose before and daily for 3 weeks after surgery, but the dose rate was not controlled according to INR.

Pinto (1970; https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1002/bjs.1800570508) in Controlled trial of an anticoagulant (warfarin sodium) in the prevention of venous thrombosis following hip surgery. “Fifty consecutive patients over the age of 50 years, undergoing hip operations, were studied. Twenty-five patients were treated with warfarin sodium and 25 acted as controls. Nine in the treated group and 8 in the control group developed postoperative deep-vein thrombosis.”

Sachs et al (2003; https://www.sciencedirect.com/science/article/abs/pii/S0883540303000718) in Does anticoagulation do more harm than good?: A comparison of patients treated without prophylaxis and patients treated with low-dose warfarin after total knee arthroplasty. Abstract excerpt: “The control group had a total complication rate of 2.2%, with a death rate from thromboembolic disease of 0.0% and a total death rate of 0.2%. The warfarin group had a total complication rate of 4.7%, with a death rate from thromboembolic disease of 0.0% and a total death rate of 0.1%. Both deaths in the control group were from cardiac disease, while the death in the warfarin group was due to a massive gastrointestinal bleeding. The warfarin group had twice the infection rate of the control group.”  

Ballal et al (2020; https://ard.bmj.com/content/80/5/605.abstract) in Warfarin use and risk of knee and hip replacements. Conclusion “Warfarin, a vitamin K antagonist, was associated with greater risk of KR and HR (an indicator for end-stage knee OA) than DOAC use, supporting the importance of adequate vitamin K functioning in limiting OA progression.”

The following article using dextran40 as a control suggests that warfarin was better than dextran40, but I prefer no-treatment controls.

Francis et al (1983; https://jamanetwork.com/journals/jama/article-abstract/382260) in Two-Step Warfarin TherapyPrevention of Postoperative Venous Thrombosis Without Excessive Bleeding. This study of patients prone to venous thrombosis, used a course of warfarin for 10-14 days before surgery and used dextran 40 for controls. The clinical results were better for warfarin.

Bingham et al (2018; https://www.sciencedirect.com/science/article/pii/S2352344118300475) in A dedicated anticoagulation clinic does not improve postoperative management of warfarin after total joint arthroplasty. Conclusions: “Despite utilization of a dedicated anticoagulation clinic, patients were only within their target INR range 27% of the time. Total knee arthroplasty patients who developed a PJI were more likely to be therapeutic or supratherapeutic in the initial postoperative period. Consequently, the risks associated with warfarin as a venous thromboembolism prophylaxis may outweigh the potential benefits.” This paper suggests that too much warfarin is associated with periprosthetic joint infections.

It's hard to draw conclusions from the above literature.

Prometheus, you may notice that in the conclusion by Ballal et al above, there is a phrase “ ... supporting the importance of adequate vitamin K functioning in limiting OA progression.” There is mounting evidence that many conditions, including osteo-arthritis, are associated with low vitamin K status.

 

I’ll append a few references to that:

 

Neogi et al (2006; https://onlinelibrary.wiley.com/doi/full/10.1002/art.21735) concluded that there was a significant association between low plasma phylloquinone concentrations and increased prevalence of osteoarthritis manifestations in the hand and knee.

Shea and Booth (2017; https://www.sciencedirect.com/science/article/pii/B9780128051863000199) reviewed vitamin K and knee osteoarthritis and concluded that vitamin K–dependent proteins in joint tissues from patients with osteoarthritis were undercarboxylated (therefore less functional), and that lower vitamin K nutritional status was associated with more osteoarthritis. They affirmed in this 2017 review that no clinical trials have yet been designed specifically to test the effect of vitamin K supplementation on osteoarthritis.

Kok-Yong Chin (2020; https://www.mdpi.com/2072-6643/12/5/1208) reviewed the literature on Vitamin K status and osteoarthritis and concluded that it generally suggests that a low vitamin K status is associated with the condition, particularly in the elderly, but that sufficient trials have not yet been conducted to determine optimal doses of vitamin K.

Laio et al (2020; https://www.oarsijournal.com/article/S1063-4584(20)30836-0/abstract) reported on 213 patients with symptomatic knee OA and low 25-hydroxyvitamin D (12.5-60 nmol/L) who finished the study and who were enrolled and randomly assigned to receive monthly treatment with oral 50000 IU vitamin D3 or an identical placebo for 2 years. Their dietary vitamin K intakes were evaluated, and they were classified as 'high' if above 112 micrograms a day on average or 'low' if below that average. Their baseline WOMAC scores for arthritis were assessed at baseline and after 24 months. The 'high' vitamin K with sufficient vitamin D groups showed significant improvements over their baseline figures for Womac scores in 'Total Score', 'Pain Score', 'Function Score', and approached significance in 'Stiffness Score'.

Boer et al (2020; https://www.oarsijournal.com/article/S1063-4584(20)30700-7/abstract) showed that a vitamin K antagonist, acenocoumarol, resulted in a two-fold increase in hip and knee osteoarthritis when used for longer than 100 days. The same effect was not produced with anti-platelet medication.

.....................................

It is the sort of literature I’ve listed above that makes me question whether anybody has checked on the association between vitamin K supplementation and deep vein thrombosis. Few of my contacts are aware that vitamin Ks activate two very powerful anticoagulants in the form Proteins C and S.

[Doogles31731]

18 hours ago, exchemist said:

Try this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911546/

I quote: "The effect of gross changes in vitamin K intake on anticoagulation is a classic. Since the early years of warfarin use myriad case reports and case series have described decreased anticoagulant response due to sudden excessive vitamin K intake. The causes were usually vitamin K rich, vegetable-based, weight reducing diets and food supplements or multivitamins. The culprit amounts of vitamin K consumed ranged from 25 to 6000 µg day⁻¹, but other causes for therapeutic failures were not always excluded [28–31]. Excessive anticoagulation has also been described after unrecorded dietary modification or discontinuation of multivitamin use [31, 32]. 

Suggest following up these references if you are interested.

But I would observe you did this with climate change as well. You jumped to the conclusion that the findings were an "assumption" and that some crucial piece of experimental work had not been done, when the problem was your own lack of understanding of the relevant science background. I suggest you would do better to ask your questions before you start drawing conclusions that there is something wrong with the science.

 

exchemist, I studied the article. My interpretation of ‘therapeutic failure’ is that it refers to difficulty in controlling INR due to diets containing warfarin antagonists or supplements containing vitamin K. I checked the refs listed in your excerpt.

Ref 28 - One patient had warfarin-resistance because her diet contained 1300 micrograms vitamin K

Ref 29 - One lady had a myocardial infarction. The full text was not readily available. (Vitamin K deficiency has been associated with coronary heart disease.)

Ref 30 - The Abstract virtually states that vitamin K can interfere with warfarin effects.

Ref 31 - This could be contentious - There was a fall in INR associated with thrombosis and haemorrhage in a couple of patients after a multivitamin supplement containing only 25 micrograms of vitamin K1. “Suspecting vitamin K1 deficiency as an explanation for this oversensitivity, we assessed the prevalence of vitamin K1 deficiency in our clinic by determining plasma vitamin K1 levels in 179 stable consecutive patients, finding very low levels (<0.1 ng/mL) in 22 of 179 (12%).”

Ref 32 - suggests that dietary modifications of many kinds, including vitamin K-rich foods may affect anti-coagulants.

Ref 35 - “We now have solid prospective clinical evidence that modulation of dietary vitamin K is a feasible approach to reach anticoagulation stability. Our data indicate that changes in dietary vitamin K intake are an efficacious strategy to increase the probability of achieving INRs within the therapeutic range.”

Re the article itself, it basically suggests that genetics are the main contributing factors to the variability of INR readings for patients on warfarin, but that variations in diet and particularly in vitamin K concentrations can also be involved.

Some significant excerpts -- “In this context it is important to note that many patients are still instructed, at the onset of therapy, to restrict and even avoid vitamin K consumption. This could be reflected in the rates of low dietary intake or of biochemical vitamin K depletion, demonstrated in warfarin treated patients in different countries [31], as contributing to clinically significant day to day within-patient variability in INR response, during long term treatment [35]”

“ a recent study aimed at long-term warfarin treated patients, demonstrated that an intervention based on structured vitamin-K dietary instructions could improve returning INR levels to within the therapeutic range, following detection of sub-therapeutic values [35].”

“Several studies have addressed the effects of supplemental vitamin K on response to warfarin. Thus, single dose administration of a 250 µg vitamin K1 tablet to patients stabilized on warfarin did not result in prothrombin times outside the therapeutic range. However, after 1 week of daily administration of the vitamin, increased doses of warfarin were required in order to maintain the therapeutic range, and doses of K1 tablets at 100 µg day⁻¹ for 1 week caused increased coagulability, but still within the therapeutic range [38].”

I found the paper interesting even though it was not what I was looking for. It was news to me that anybody would recommend supplementing warfarin therapy with vitamin K1, especially with a dose of 250 micrograms. I see that as a good idea considering the importance of vitamin Ks in general health.

But it still does not represent experimental evidence that high vitamin K is associated with the formation of deep vein thrombosis and emboli.

So, following my (apparently badly drafted) question in the OP as to whether anyone knew of evidence that vitamin K in excess of physiological requirements is associated with emboli or deep vein thrombosis, it is becoming more apparent that the answer is in the negative.

 

[Prometheus]

7 hours ago, Doogles31731 said:

It's hard to draw conclusions from the above literature.

It's not surprising as they are assessing different things: 2 looked at warfarin for thromboembolism (surprised this was still being looked at in 2003), 1 at warfarin risk of arthritis and 2 at particular dosing regimens for peri-operative care in high risk populations. 

 

7 hours ago, Doogles31731 said:

...but I prefer no-treatment controls.

You'll be hard pressed to find many such studies as its deemed unethical to have no-treatment controls when there is a known viable treatment. To find such you'll have to look at some very old studies, maybe the clinical trial data submitted to the FDA in the first instance. 

 

7 hours ago, Doogles31731 said:

It is the sort of literature I’ve listed above that makes me question whether anybody has checked on the association between vitamin K supplementation and deep vein thrombosis.

But what do you actually want to know? This statement makes it seem like you are interested in the role of dietary vitamin K and DVT. If this is the case, pursuing the warfarin literature (though it might be where you got your initial idea, and have implications for it) is a red herring. Isolate the precise clinical question you want to answer, something like does increased vitamin K increase risk of DVT? If so, what is the likely causal mechanism? Restrict your question to as few variables as possible: once you have a handle on that, you might consider another variable and so on...

[Doogles31731]

Thank you Prometheus for your time, your consideration and your suggestions. I appreciate your responses. I think some background on my interest in vitamin K will clarify my position.

In actual fact, a study of vitamin K and its functions have become something of a hobby of mine over the last seven or so years. I have studied hundreds of articles over this time period and have actually produced a dissertation on the benefits of high doses of supplementation that is totally evidence-based and which contains over 200 hyperlinks to original research.

I was on crutches seven years ago because of developing osteoarthritis of the right ankle and heading for a wheelchair. I’ve had bilateral knee replacements for 17 years. I have a stent in a heart artery and a pacemaker for almost as long, and was starting to get mild anginas at the start of exercising, as well as lumbar back pain.

Ultrasounds of my lower aorta and bilateral leg arteries revealed that I had extensive atherosclerosis of most arteries and that some were occluded. I received the results weeks before the next scheduled visit to the vascular surgeon who prescribed the ultrasounds, so in the meantime, I began to research all the literature I could on osteoarthritis and atherosclerosis.

I discovered that arteriosclerosis and atherosclerosis had been reproduced experimentally in pigs, dogs, rabbits and rats for decades. One study caught my attention. The authors primed rats with high doses of vitamin K and vitamin E prior to experimentation, only to discover that it prevented them from reproducing the condition. My natural consideration was that if these vitamins prevented the condition, they may just have some therapeutic effect. I’d already been taking some Vitamin E.

My extensive reading suggested that vitamin K was extremely safe, to the extent that it may be one of the safest substances on the planet, that the recommended daily allowance was far too low, and that for a holistic effect, it was necessary to take both vitamin K1 and K2. I settled on 500 micrograms each of K1 and K2-MK4 for the last 7+ years.

My right ankle pain on weight-bearing disappeared within 3 weeks, so the crutches were discarded. My anginas disappeared, as did my back pain. Ultrasounds of my lower aorta and leg arteries 14 months later showed normal tracings for any arteries less than 60% stenosed. Occluded arteries have remained occluded. Although my right ankle recovered enough for painless weight-bearing, both ankles are structurally disgraceful; flattened as in ‘Charcot’s Foot’, and there is still a 2.5 cm osteophyte on the medial aspect of the right ankle.

I will attempt to upload an image of the ultrasounds of my lower aorta before and after high vitamin K supplements for 14 months. I believe it is the only evidence in the world of reversal of atherosclerosis.

I’ve been trying to rationalize exchemist’s unusual response to my OP, and I believe it may be that I am now on a different page from other people with respect to vitamin K. I have conducted all my own research and experimentation solo by just following the literature references. My own GP changes the subject any time I attempt to discuss it. My cardiologist, foot specialist, pharmacist and other health industry workers all tell me that the vitamin K will ‘thicken’ my blood and cause blood clots. Hence my opening statement. It may be that this mindset may not be present in heath practitioners in other parts of the world.

I was thinking about how widely warfarin has been, and still is, used, these days in cases where my research suggests high vitamin Ks should be prescribed. I have so far identified 17 medical conditions associated with low vitamin K status (variously low, moderate or strong associations). Recently I was reading about warfarin and deep vein thrombosis when it occurred to me that therapists would not be using warfarin (a vitamin K antagonist) unless they thought that vitamin K in excess of physiological requirements was associated with that condition. I searched for literature associating vitamin K with deep vein thrombi or emboli without success, and posted in this forum to check whether I had missed something.

My dissertation consists of 120 odd pages, so the above just barely touches on the subject.

[Prometheus]

9 hours ago, Doogles31731 said:

I think some background on my interest in vitamin K will clarify my position.

I'm afraid it only obfuscates. Try this; give yourself just one sentence in which to express the particular problem you want to investigate. The last sentence of your last sentence seems close.

[Doogles31731]

Thanks again Prometheus.

I'll try this. It will broaden the context.

I searched for literature associating vitamin K with deep vein thrombi or emboli without success, and posted in this forum to check whether I had missed something.

Can any member of this forum locate any practical research evidence of any kind indicating that vitamin K supplements in excess of physiological requirements will exacerbate any form of blood coagulopathy including deep vein thrombosis, emboli, or disseminated vascular coagulation from any cause?

I'm not looking for the theoretical answer that because vitamin Ks activate proteins involved in the cascade of steps involved in the process of blood clotting, that it must be involved. 

[Prometheus]

In 3 minutes of searching all i could find was related to vitamin k deficiency rather than excess supplementation. If there is any specific literature out there it's likely to be buried in the vast coagulopathy literature. requiring a formal systematic literature review.  It's a very niche interest, might be best asking a haemotologist who has an interest in dietary concerns. Good luck.

[Doogles31731]

Apologies for the length of this post, and particularly if you already know all about the subject.

Thanks again Prometheus. Even though you spent only 3 minutes researching, I believe it’s now safe to say that no research group appears to have assessed the effects of high vitamin K supplementation on blood coagulopathies. I couldn’t find any such evidence in the literature and I didn’t want to make such a statement, unless someone else affirmed it. You and exchemist have done so to some extent. 

I think it is noteworthy that you found references only to low, as distinct from high, vitamin Ks.

By 2012, Theuwissen et al (http://advances.nutrition.org/content/3/2/166.full) concluded that there is no such thing as healthy human subjects with fully carboxylated-glutamic acid-proteins outside of the liver and that western diets contained insufficient vitamin K to meet the requirements of healthy bone and vascular wall.

This was a reinforcement to some extent of the opinion of Shearer & Newman (2008; https://www.thieme-connect.com/products/ejournals/abstract/10.1160/TH08-03-0147) who stated that data on the bioavailability of the various forms of vitamin K is limited, and that although the absorption of pure vitamin K1 is 80%, the absorption from foods such as spinach is only 4-17% of that absorbed from tablets because of its tight binding to chloroplasts.

If those studies are correct, then the comparisons of association with various degenerative diseases in the literature is tantamount to a comparison of low low with moderately low blood concentrations of the biomarkers. As I said in an earlier post, a study of vitamin K and its association with degenerative diseases has become almost a hobby of mine over the last 7+ years.

The recommended daily allowance of vitamin Ks (roughly 100 micrograms) is apparently based on the amount required to produce adequate blood coagulation (Shearer et al 2012; https://academic.oup.com/advances/article/3/2/182/4557941).The role of vitamin Ks in blood coagulation is only a part of its usefulness. It plays a vital role in brain development and function (Ferland 2012; https://academic.oup.com/advances/article/3/2/204/4557944) and most importantly in blood vessel health. ‘Low’ vitamin K status has been associated with blood vessel integrity in the form of arteriosclerosis and atherosclerosis (Jie et al 1995; http://www.sciencedirect.com/science/article/pii/0021915095055377; Knapen et al 2015; https://www.thieme-connect.de/DOI/DOI?10.1160/TH14-08-0675; Vissers et al 2016; https://www.atherosclerosis-journal.com/article/S0021-9150(16)31216-3/abstract; Lees et al; 2018; https://heart.bmj.com/content/105/12/938.abstract). And atherosclerosis has been associated with many conditions, including osteoarthritis, coronary heart disease, chronic kidney disease, dementia, atrial fibrillation and strokes. You can check all of the latter simply by using the ‘keywords of the condition’ and ‘atherosclerosis’ into Google Scholar.

Although vitamin K is well known as an activator of factors involved in the blood clotting cascade, it is not well known that it also activates at least two anti-coagulant proteins in the form of Protein C and Protein S. After Protein C is activated by vitamin K as a co-factor, it undergoes further activation by combining with a thrombin-thrombomodulin combination, plus its own receptor on the endothelium, to form a very powerful complex known as Activated Protein C (APC), which is further activated many-fold by Protein S. Maruyama (1999; https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0037-1615902) in Recombinant Thrombomodulin and Activated Protein C in the Treatment of Disseminated Intravascular Coagulation, explains it in more detail.

This APC is intimately involved in controlling the degree to which blood-clotting mechanisms work, as well as preventing several stages of atheroma formation -- it counteracts the vascular adhesive proteins that cause monocytes to stick to the endothelium of arteries; it counteracts the chemattractants that cause monocytes to infiltrate between endothelial cells to lodge in the intima as they differentiate into macrophages and foam cells, and it counteracts some of the inflammatory products of atheroma formation. I uploaded an ultrasound image of reversal of atherosclerosis in my lower aorta in a previous post after taking high doses of vitamin K supplements..

When you consider that we have probably thousands of kilometres of blood vessels, if laid end to end (Blood Vessels | The Franklin Institute (fi.edu)), you can imagine how much APC, and therefore vitamin K, is required for general health, apart from being a blood-clotting regulator.

It explains why so much calcification of arteries is associated with prolonged warfarin medication. The following 2021 references are just a few:
Elango et al (2021; https://www.mdpi.com/2073-4409/10/4/773) in The Effects of Warfarin and Direct Oral Anticoagulants on Systemic Vascular Calcification: A Review concluded -- “ ... Established adverse effects include bleeding, skin necrosis, teratogenicity during pregnancy, cholesterol embolization, and nephropathy. One of the lesser-known long-term side effects of warfarin is an increase in systemic arterial calcification. This is significant due to the association between vascular calcification and cardiovascular morbidity and mortality. Direct oral anticoagulants (DOACs) have gained prominence in recent years, as they require less frequent monitoring and have a superior side effect profile to warfarin, specifically in relation to major bleeding. ... “

Vernados et al (2021; https://www.sciencedirect.com/scienc...03497521007268) in Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and β-catenin Signaling

Sadioglu et al (2021; https://journals.tubitak.gov.tr/medi...t.htm?id=30049) in Warfarin is associated with the risk of vascular calcification in abdominal aorta in hemodialysis patients: a multicenter case-control study

Van den Bergh et al (2021; https://www.mdpi.com/1422-0067/22/21/11615) in Endothelial Contribution to Warfarin-Induced Arterial Media Calcification in Mice

Nuotio et al (2021; https://www.frontiersin.org/articles...21.696244/full) in Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification

van gorp et al (2021; https://academic.oup.com/ehjopen/art...455?login=true) in Vitamin K antagonist use induces calcification and atherosclerotic plaque progression resulting in increased hypercoagulability

One of the positives of becoming involved in a forum such as this one is that you can always learn something and it can always stimulate some lateral thinking. When I received a useful research article from exchemist, I noted this statement “Several studies have addressed the effects of supplemental vitamin K on response to warfarin. Thus, single dose administration of a 250 µg vitamin K1 tablet to patients stabilized on warfarin did not result in prothrombin times outside the therapeutic range. However, after 1 week of daily administration of the vitamin, increased doses of warfarin were required in order to maintain the therapeutic range, and doses of K1 tablets at 100 µg day⁻¹ for 1 week caused increased coagulability, but still within the therapeutic range [38].” The danger of warfarin medication is shown by the number of complications involving artery health. It may help prevent clotting, but it also may have a tendency to reduce the activation of proteins essential for brain and artery health. I would think that this idea of supplementation of warfarin with some vitamin Ks is worth further exploration for patients on warfarin.

Another aspect that the comments of Prometheus and exchemist triggered laterally in my mind was that APC has been trialed therapeutically in a few conditions.

Over 30 years ago, Okijama et al (1990; https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.2830330413) in Treatment of patients with disseminated intravascular coagulation by protein C, described its successful use on three cases of disseminated intravascular coagulation in which heparin was not successful.

Griffin et al (2002; https://www.sciencedirect.com/science/article/abs/pii/S0037196302500470) in Activated protein 😄 Potential therapy for severe sepsis, thrombosis, and stroke, found that “Activated protein C (APC) reduced all-cause 28-day mortality by 19% in patients with severe sepsis (sepsis associated with acute organ dysfunction) in the Protein C Evaluation in Severe Sepsis (PROWESS) trial, leading to recent approval of recombinant APC for treatment of this condition in adults. This review summarizes current knowledge derived from studies of a variety of animal models in which infused human APC demonstrated beneficial activities. Based on in vivo and also in vitro data, APC manifests antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic activities.  ... “

But this article suggests a limitation -- Ikezoe (2015; https://link.springer.com/article/10.1186/s40560-014-0050-7) in Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation, summarised that “ ... On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. ... “

I know that it’s presumptuous for someone who is not involved in a particular field of endeavour to make suggestions in that field, but it does seem plausible to me to provide more blood-clotting capacity to patients if the current medication is causing hemorrhages. You can’t be executed these days for proposing an idea. Or can you???

Rather than just use APC, which must cost a small fortune to prepare, or other anticoagulants for coagulopathies, why not assess high doses of vitamin Ks. There are a number of animal models that could be used for cautious trials.

Vitamin Ks are extremely safe (refs can be supplied), cheap and available over the counter.

As far as other degenerative conditions are concerned, I must add that during my 7+ years of researching hundreds of therapeutic trials with vitamin K supplements, I have come across only one trial so far that has ensured an adequate vitamin D status in subjects. Adequate vitamin D is necessary for the synthesis of most of the proteins that have to be activated by vitamin K. Another criticism is that most trials have used either vitamin K1 or vitamin K2 instead of both; there is evidence that phylloquinone (K1), for example, will not control atherosclerosis but menaquinone (K2) will; and most trials have used too low a dose of supplements.

As a practicing veterinarian for 25 years up to 1980, I never diagnosed a coagulopathy in an animal, but if I did now, I wouldn’t hesitate to supplement it with vitamins D, K1 and K2.