Vitamin K2 - 45 mg still largest dose I've found.

Article got long - main points the Life Extension product is our best bet so far/still for Vit K2 supplementation or eat a 1/2 cup of Natto fresh per day. Also, Mega SporeBiotic by Microbiome Labs

…probiotic supplement of spore forming bacteria by Microbiome Labs, includes the species used in the fermentation of Natto, Bacillus subtilis. I have used and like the product. People with histamine excess/ Mast cell overactivity, really can’t use fermented products in my personal experience. Even tiny servings will cause negative symptoms for me (which can include crazy mental symptoms, not just a runny nose or dry itchy eyes).

The Life Extension product that I would be recommending at this time, highest dose that I can find - “Mega Vitamin K2”, (Currently on sale: lifeextension.com). *Gelatin capsules do concern me as a potential glyphosate source though. Taking one-two 45 mg in the am and pm would be approaching the lower end of the dosing range suggested for a human clinical trial based on dosing used in an animal-based study which showed efficacy.* (Previous post)

*I’m posting this rather than let it sit in draft bin waiting for better organization.

Dose matters - no efficacy found for vitamin K2 at reversing calcification.... with a minimal dose of 360 micrograms three times a week - slightly more than 1 mg per week for 18 months = 72 weeks, 72 mg. You might as well sprinkle pixie dust on the experimental group. n=89 control & 89 experimental, "Vascular Calcification in Hemodialysis Patients"

"Patients in the intervention group received oral vitamin K2 (isoform MK-7) at a fixed dose of 360 μg 3 times weekly with their HD sessions for a total duration of 18 months in addition to standard clinical care, whereas the control group received standard clinical care alone." https://sciencedirect.com/science/article/pii/S2468024923013566…

Another study using a Natto derived supplement containing 360 mcg of vitamin K2 for 12 months found no significant benefit for increasing bone strength in postmenopausal Norwegian women. (Emaus, et al., 2010) Pixie dust!

How much vitamin K2 might a person eat if they simply ate fermented Natto soybeans? Bing (the dumbest AI in my personal opinion) offers a summary which is directly plagiarizing the source. Bing: “Fermented soybeans (Natto), a traditional Japanese food, contain more than 100 times as much vitamin K2 as various cheeses and are considered to promote gamma-carboxylation. Thus it is conceivable that Natto may play a preventive role in the development of osteoporosis.” Search link: “Fermented soybeans (Natto), a traditional Japanese food, contain more than 100 times as much vitamin K2 as various cheeses and are considered to promote gamma-carboxylation. Thus it is conceivable that Natto may play “a preventive role in the development of osteoporosis.” (Katsuyama, et al., 2002) Paywall, they don’t mention a specific mcg/mg amount of vitamin K2.

The other search result from Bing is helpful in that it looked at why eating Natto was more health protective than eating Miso - both are fermented soy products, but Natto is fermented with a bacterial species which produces vitamin K2, while the fungal species used to make Miso, do not also make vitamin K2. Other research teams have suggested the protective difference is in the nattokinase produced during the fermentation process of Natto. A letter to the editor points out that vitamin K2 could be the protective difference between Natto consumption and Miso consumption.

“Dear Editor
In their epidemiological study of soy intakes and mortality, Katagiri et al reported that higher intakes of fermented soy foods (represented by miso and natto) were associated with a lower risk of all-cause mortality in both men and women (1). Sub-analysis showed that intakes of natto but not miso were significantly and inversely associated with cardiovascular disease-related mortality. In their interpretation of cause-specific mortality, the authors speculated that the lack of benefit of miso might be due to its high sodium content but did not comment on possible reasons for the cardiovascular protective benefits of natto. Natto differs from miso in that fermentation of the soybeans is by a bacterium rather than a fungus. The species (Bacillus subtilis) used for this fermentation is a vitamin K-synthesising bacterium which results in natto containing very high concentrations (800-1000 µg/100g) of the vitamin K2 form menaquinone-7 (MK-7), as well as an enzyme called nattokinase. Neither of these components is present in miso.” (Lowis, 2020)

*a Consultant Paediatrician, Martin Shearer Honorary Consultant Scientist, Centre for Haemostasis and Thrombosis, Guy's and St Thomas' NHS Foundation Trust Dominic Harrington Chief Scientific Officer, Pathology (Viapath), Guy's and St Thomas' NHS Foundation Trust, Bristol Royal Hospital for Children, Upper Maudlin St, Bristol ← maybe we should listen to him.

That gives us a dietary baseline - eating 100 grams, about 3 ounces, not quite a half cup serving of fermented soybeans per day, would provide about 800-1000 mcg of vitamin K2 - roughly a milligram. So, the 45 mg Life Extension supplement of vitamin K2 would be ~ the equivalent of eating 135 ounces (~ 8.5 pounds) of fermented soybeans per day (*not a dietary recommendation, a math game for dietitians).

We learn that nattokinase has not been shown to be well absorbed - (it protects the gut, but may not be effective against spike within the bloodstream).

“Katagiri et al cite a recent study by Nagata et al that had also reported a lower risk of cardiovascular mortality in Japanese people who ate natto (2). Nagata et al. considered that the efficacy of natto might be attributed to the fibrinolytic properties of the enzyme nattokinase. The problem with this nattokinase hypothesis is that despite its fibrinolytic activity in vitro, there is no evidence that this enzyme can be absorbed in its intact active form from the intestinal tract. We wish to propose an alternative explanation which is that the benefits to cardiovascular health largely accrue from the high MK-7 content of natto. Unlike nattokinase, MK-7 is known to be well absorbed and has a much longer plasma half-life and greater tissue retention than phylloquinone (vitamin K1, the major dietary form of vitamin K in most populations (3).” (Lowis, 2020)

Why should we care about vitamin K2? Because it has been shown to be effective in a fairly large number of studies for protecting against soft tissue calcification.

“There is a compelling body of evidence which relates phylloquinone and menaquinone intake as well as vitamin K status to cardiovascular morbidity and mortality. (4–7). A recent systematic review by Lees et al reported significant correlation of (reduced) cardiovascular disease and mortality with vitamin K-dependent proteins in patients receiving MK-7 supplementation. (8)” (Lowis, 2020)

The rest of his letter … because it is important.

“There is a plethora of vitamin K-dependent (VKD) proteins in the body with a variety of functions, of which the best known are procoagulant (factors II. VII, IX and X) or anticoagulant proteins (protein C and S), exclusively or mainly synthesised in the liver. Other VKD proteins such as osteocalcin, matrix Gla protein (MGP) and Gla-rich protein are synthesised in extrahepatic tissues and are known to play roles in calcification processes in the bone and vasculature. Although vitamin K is essential for the gamma-glutamyl carboxylation of all these proteins, there is good evidence that the dietary amounts of vitamin K needed to ensure sufficient carboxylation of extrahepatic VKD-proteins are higher than those needed for the hepatic coagulation proteins (3). The knowledge that VKD-proteins that are undercarboxylated are either inactive, or less biologically active, is therefore one mechanism whereby suboptimal intakes of vitamin K can adversely affect cardiovascular health. In this regard, there is increasing evidence that MGP and other VKD proteins are major players in the pathology of cardiovascular calcification (9). Based on this increased mechanistic understanding, several trials are already under way to test the effect of vitamin K supplementation on cardiovascular health outcomes (9). Future studies should also investigate the mechanisms of the associations of soy intakes with mortality as reported by Katagiri et al. Natto is a cheap and plentiful foodstuff. Investigation of the mechanisms for such associations offers significant potential for improved cardiovascular health.” (Lowis, 2020)

The take-home point seems to be that more vitamin K2 is quite protective and minimally/traditionally, about 1 milligram per day might be significant, one side-dish serving of fermented Natto soybeans. That is about three times more than the ‘didn’t help much’ 360 mcg experimental dose.

The second take-home point - having beneficial gut microbiome species is key, because some of the species can make it for us, and also are making it for other beneficial species who need it but maybe don’t make it as well. Gut microbiome species are a collective in many ways, rather than single species doing their own solitary thing. How can we promote vitamin K2 formation within our gut? Eating the live culture fermented soybeans, Natto, would be seeding the gut with some of that bacterial strain, promoting its growth within the gut too. Bacillus subtilis is a spore forming bacteria that wouldn’t be in most ‘probiotic’ supplements available for purchase but is included in a shelf-stable product by Microbiome Labs called Mega SporeBiotic. Their protocol suggests a few months with stages of products, and then tapering off, rather than ‘for-life’ use. They recommend starting with the SporeBiotic product as those species help support the growth of other beneficial species…maybe by making vitamin K2. (microbiomelabs.com) I have used this product and liked the company enough to become an affiliate *only applicable for private/individual patient contact with me, which I am not offering at this time). It is also available through Fullscript which I am also an affiliate with.

These ‘pixie dust’ nutrient studies are the sort of bad nutritional study that sets back the whole field when "no efficacy" is found…. with a tiny amount. Or sometimes a huge amount causes negative "side effects” (I saw that with a flush niacin study that started people at 500 mg (x 3 maybe) right out of the door, with no gradual increase…. people would hate that).

A “pixie-dust” food product - dried powdered Natto is being sold for $110.59 for 300 grams and the recommendation is to take 1-2 grams per day. It is simply dried, powdered Natto, so it is no longer a live culture product but might have some spores of the Bacillus subtilis. Bacterial spores are like bacteria eggshells kind of - able to survive in dried out conditions, and then start growing again once in a wet environment. My point in calling it pixie-dust (and expensive) - from my own measurements of fresh pomegranate peel and dried, about half the weight is lost, so roughly, 300 grams of Natto powder represents 600 grams of fresh Natto which would contain roughly (800-1000 mcg vit K2/100 grams) 4800-6000 mcg of vitamin K2, in the whole package. Their recommended dose of 1-2 grams might be providing 20-40 mcg of vitamin K2 per day (6000/150-300). To get one milligram you would need to eat about a sixth of the package, a sixth of the 300 grams.

Incidentally, Bifidobacterium species also make some vitamin K2, so chimeric spike selectively knocking out Bifidobacterium species is also likely causing vitamin K2 deficiency. *I think that is from a different draft post, I am behind on posting a few things.

I saw 45 mg as a dose used in a Japanese study - Life Extension article promoting a product, https://lifeextension.com/magazine/2020/ss/vitamin-k2-builds-new-bone…. , Life Extension sells a "Mega K2" capsule with 45 mg which I do use. I’m never sure if ‘gelatin’ capsule is a glyphosate source though.

Two of those capsules would provide more vitamin K2 than the experimental group got in the whole 18 months in the 360 mcg study. https://sciencedirect.com/science/article/pii/S2468024923013566…

A Thorne liquid drops vitamin K2 product:

Thorne - 1 mg per drop, they recommend 15 drops as a serving, 1 ounce bottle provide 80 servings at 15 mg/15 drops each. $72 for 1200 mg based on the serving count. To get a one-gram amount using that product, I would need to take 5/6ths of the bottle every day. https://amazon.com/Thorne-Research-Vitamin-Liquid-drop/dp/B000FGWDTK… Do you see the problem?

An additional unknown with that product, it contains Other Ingredients: Mixed Tocopherols with no specified amount - vitamin E, which acts as a preservative. BUT Too much vitamin E could increase bleeding risk. How much tocopherols would be in 5/6ths of the bottle? And using that much would cost $60/day.

“Magical Thinking” a sprinkle of pixie dust on my diet will turn my life around and decalcify my blood vessels!

Addition (took an Epsom salt bath and feel better now).

“Seeding and Feeding” = Probiotics and prebiotics = live culture or spore products and fiber/resistant starches, zinc and other minerals.

The Microbiome Labs approach in having stages of gut repair products, that aren’t intended to be needed forever, includes making diet and lifestyle changes that help support a healthy gut microbiome into the future, with a balanced variety of species established from the phases of products. Live culture, yogurt type of foods or supplements, have bacteria that are aerobic, small intestine colonizers. Eating yogurt, live culture sauerkraut, or kefir and kombucha drinks, help to replenish or establish those species. Lactobacillus species are common. Eat dirt? The spore Bacillus species tend to be soil bacteria.

Allegedly (alien communication/tinfoil) the initial human GMO project included some Earth soil bacteria to help promote coping/adapting to life on the planet, in addition genetic donations from a few alien species and Earth primates. I don’t know what I don’t know, but I do know that humans are in a symbiotic relationship with our gut microbiome. Harming our gut microbiome is harming part of ourselves.

Product review on Fullscript found that they don’t carry the highest dose K2 product offered by Life Extension - join their site and buy direct “Mega Vitamin K2”, (on sale currently for $25.65/30 gelatin capsules, or 4 bottles at $23.40. Membership might be needed but you get bonus dollars for free product/off the cost of a bill, lifeextension.com), not Super K or Low K. Fullscript does carry a DaVinci brand product with 500 mcg of K2 and 50 mg of resveratrol in a vegetable cellulose capsule. No other products have much more than 100-200 mcg and many are below 100 mcg.

Aside/ I noticed that high dose niacin is simply not available for purchase on Fullscript either. They do carry high dose iodine, Iodoral, though. When the market is controlling the range of choices, then the patient population who is being recommended that dispensary is going to be underserved potentially, on average - all the participating doctors or other affiliated health professionals may be making recommendations limited to the range being offered.

A Dietary Supplement to Support Healthy Bone Mineral Density*
As a dietary supplement, take 1 capsule daily, or as directed by your healthcare practitioner. Serving Size: 1 Capsule,
Amount Per Serving
Vitamin K2 ... 500mcg
(as Menaquinone-7)
Polygonum caspidatum Root Extract ... 100mg
(yieling trans-resveratrol 50mg)
Other Ingredients: microcrystalline cellulose, vegetable cellulose (capsule), vegetarian leucine.
Warning: If pregnant or nursing, consult your
healthcare practitioner before taking this product.
Caution: Discontinue 2 weeks prior to surgery.

Another organization, the International Life Sciences Institute, (ILSI Europe) has made a recommendation that vitamin K and vitamin K2 should both be considered when calculating dietary goals.

“In recognition of the effect of VK₂ on reducing the risk of coronary heart disease, the International Life Sciences Institute (ILSI Europe), recently recommended taking VK₂, in addition toVK₁, into consideration when calculating the daily recommended value of vitamin K.^61” (El Asmar, et al., 2014)

Pixie-dust amounts of vitamin K2 were not found helpful, but doses near or higher (360 mcg/day) than the current recommendations were found helpful against vascular calcification biomarkers in patients receiving hemodialysis. Lower doses do not seem to be adequate to activate vitamin K dependent proteins (VKDPs).

“A study on hemodialysis patients subjected to varying doses of mk-7 intake resulted in a decrease in serum dp-ucMGP, ucOC and PIVKA-II levels significantly in the group treated with 360 microgram/day, but not at lower doses.²⁹ In order to sufficiently carboxylate peripheral VKDPs, VK₂ is needed at doses near to/or higher than the currently accepted RDA value. The administration of MK-7 reduced ucMGP and dp-ucOC levels significantly at doses near RDA but not significantly at lower doses.^67” (El Asmar, et al., 2014)

MGP is one of the vitamin K2 dependent proteins (VKDPs) - without vitamin K2, the enzyme can’t work correctly.

“This paper will review the process of vascular calcification and delineate the role that vitamin K2 plays in the modulation of that process, through the activation of VKDPs. One such VKDP is Matrix Gla Protein (MGP), which when activated inhibits osteogenic factors, thereby inhibiting vascular and soft tissue calcification.” (El Asmar, et al., 2014)

Diabetes, and elevated blood sugar levels, increased glycation of proteins - AGEs, being made internally rather than obtained from crispy dietary sources.

“Diabetic patients suffer from calcification in the tunica media mainly in the thoracic aorta, coronary arteries and tibial arteries.^68,69 The possibility of calcification in these patients is four times higher than in non-diabetics.⁷⁰ The incidence of advanced glycation end-products (AGE), which correlates with the occurrence of coronary artery calcification (CAC), may be induced by the elevated blood glucose levels.^71,72 Alternatively, calcification in these patients may be triggered by vascular inflammation or the formation of foam cells from macrophages that in turn contribute to the calcification process.⁷³ MGP levels were found to be higher in diabetic patients,³² with higher ucMGP levels indicating higher risks of mitral arterial calcification a trend that was contrary to that observed in non-diabetics.³⁵ This indicates that vitamin K dependent proteins may play a role in the observed incidence of calcification in diabetics, an effect which may be counteracted with sufficient vitamin K treatment.” (El Asmar, et al., 2014)

Phosphorus can increase calcification, so a dietary vitamin K2 supplement that is made with phosphorus filler is likely negating the value of the vitamin K2. The average diet tends to have too much phosphorus already.

“Besides carboxylating VKDPS, VK₂ may exhibit its effect by regulating gene transcription of several proteins involved in calcification. It was found to reduce the levels of osteopontin (OPN) mRNA, while increasing the expression of MGP. These trends were opposite to the ones observed when treatment with inorganic phosphate, a calcification inducer, was used.^57” (El Asmar, et al., 2014)

While I couldn’t find much on soft tissue calcification of the inner ear and Vitamin K antagonist anti-coagulant treatment, there is a very clear connection between vitamin K antagonist medications and calcification of blood vessels. *MGP has a rolein the risk.

“Vitamin K antagonists (VKA), such as warfarin and their derivatives, are administered as anticoagulants to many patients. They inhibit the recycling of vitamin K in the epoxide cycle thereby reducing its availability to carboxylate coagulation factors in the liver; however, they have a similar effect on non-hepatic vitamin-K dependent proteins.

»>VKAs were found to cause calcification in human femoral arteries,⁷⁶ mitral valves,⁷⁷ aortic valves,⁷⁷ and rat carotid artery and aorta.⁴⁹ Coronary calcification was also observed in arterial fibrillation patients with low-cardiovascular risk, as a cause of VKA treatment.⁷⁸

The administration of VKA was associated with higher MGP levels in the vasculature of rats, particularly in the calcified regions. However, a 3 fold decrease in circulating serum MGP was recorded in the treated rats, perhaps due to more MGP becoming attached to the growing crystals.⁵⁰ In human subjects, a study by Rennenberg and colleagues suggested higher levels of dephosphorylated, non-carboxylated MGP (dp-ucMGP) in patients using Coumadin for over ten years.⁷⁶ Elevated dp-ucMGP levels may indicate peripheral vitamin K deficiency and may serve as a biomarker for vascular calcification.

»>In support of this, normal subjects treated with VKA had elevated dp-ucMGP,^25,79 while those on vitamin K supplementation had decreased levels.^79” (El Asmar, et al., 2014)

Figure 4 (name, date)

Let’s play a game with PubMed.

Search term “Matrix Gla Protein in the inner ear hair cell” = zero results

“VKDP in the inner ear hair cell” = zero results

“Vitamin K Dependent Proteins in the inner ear hair cell” = zero results

“Vitamin K dependent proteins in the cochlear” = one result, (Watzka, et al., 2014) Having a dysfunctional gene affecting vitamin K2 carboxylation is associated with cochlear hearing loss and similar lack of carboxylation of MGP, osteocalcin and periostin (VKDPs) is seen in fetal development problems seen with Warfarin treatment in the pregnant woman.

Abstract: “Functional limitations for the vitamin K cycle, caused either by mutations in gamma-glutamyl carboxylase or vitamin K epoxide reductase genes, result in hereditary deficiency of vitamin K-dependent coagulation factors (VKCFD1 and VKCFD2, respectively). Patients suffering from VKCFD often share several other anatomical irregularities which are not related to haemostasis. Here we report on nine patients, eight of them previously unreported, who presented with VKCFD1. All were examined with special attention to vitamin K-dependent coagulation factors as well as to bone and heart development and to other anatomical signs of embryonal vitamin K deficiency. In total, we detected ten mutations in the gamma-glutamyl carboxylase gene of which seven have not been previously reported. Most interestingly, additional non-bleeding phenotypes were observed in all patients including midfacial hypoplasia, premature osteoporosis, cochlear hearing loss, heart valve defects, pulmonary stenosis, or pseudoxanthoma elasticum-like phenotype. Undercarboxylated matrix Gla protein, osteocalcin, and periostin appear to be responsible for these defects which are also observed in cases of fetal warfarin syndrome.” (Watzka, et al., 2014) *paywall

// related to Warfarin mechanism of action: (Mosnier, 2018; Rishavy, et al., 2018)

“osteocalcin cochlear hearing” = 127 results, mixed, not all related - that is more what I expect to see rather than ‘zero’. (pubmed)

In sudden sensorineural hearing loss lack of response to treatment was worse when biomarkers of bone turnover were elevated. A collagen biomarker (β-CTX) was more significantly related than an osteocalcin metabolite, (N-MID), but it was also correlated with non-response - worse hearing loss.

“Age, the incidence of vertigo, pure tone average of the impaired frequencies (PTA_impairedfre), and the levels of bone turnover [including alkaline phosphatase (ALP), β-carboxy terminal crosslinked telopeptide of type 1 collagen (β-CTX), and N-terminal-midfragment of osteocalcin (N-MID)] were higher in the nonresponders than responders (P < 0.05).” (Chen, et al., 2022)

“Escolha o lado Feliz da vida!” ~

“Choose the happy side of life!” - Genildo Ronchi, August 2013.

“Two Guys on a Bus” — was really one guy who changed his seat. This cartoon is by a Brazilian artist, Genildo Ronchi, about an actual bus ride that he took. He was the person sitting in gloom who then purposely moved over to the other side of the bus and got a brand-new perspective on life. A one panel cartoon later… and a meme was born. This cartoon is so powerful. (knowyourmeme.com)

Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.

Reference List

(Chen, et al., 2022) Chen X, Zheng Z, Xiao L, Liu C, Shen Y, Ma N, Dong H, Yin S, Feng Y. Bone-turnover biomarkers as potential prognostic factors in sudden sensorineural hearing loss: A prospective cohort study. Front Neurol. 2022 Aug 25;13:980150. doi: 10.3389/fneur.2022.980150. PMID: 36090873; PMCID: PMC9453032. https://pmc.ncbi.nlm.nih.gov/articles/PMC9453032/

(El Asmar, et al., 2014) El Asmar MS, Naoum JJ, Arbid EJ. Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review. Oman Med J. 2014 May;29(3):172-7. doi: 10.5001/omj.2014.44. PMID: 24936265; PMCID: PMC4052396. https://pmc.ncbi.nlm.nih.gov/articles/PMC4052396/

(Emaus, et al., 2010) Emaus N, Gjesdal CG, Almås B, Christensen M, Grimsgaard AS, Berntsen GK, Salomonsen L, Fønnebø V. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int. 2010 Oct;21(10):1731-40. doi: 10.1007/s00198-009-1126-4. Epub 2009 Nov 25. PMID: 19937427. https://link.springer.com/article/10.1007/s00198-009-1126-4

(Katsuyama, et al., 2002) Katsuyama H, Ideguchi S, Fukunaga M, Saijoh K, Sunami S. Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. J Nutr Sci Vitaminol (Tokyo). 2002 Jun;48(3):207-15. doi: 10.3177/jnsv.48.207. PMID: 12350079. https://pubmed.ncbi.nlm.nih.gov/12350079/

(Lowis, 2020) Lowis, S.P., Association of soy and fermented soy product intake with total and cause specific mortality: prospective cohort study, BMJ 2020;368:m34, doi:https://doi.org/10.1136/bmj.m34

(Mosnier, 2018) Mosnier LO. Warfarin, a juggler's demise. Blood. 2018 Jun 21;131(25):2742-2743. doi: 10.1182/blood-2018-05-843151. PMID: 29930151; PMCID: PMC6014355. https://pmc.ncbi.nlm.nih.gov/articles/PMC6014355/

(Rishavy, et al., 2018) Rishavy MA, Hallgren KW, Wilson L, Singh S, Runge KW, Berkner KL. Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase. Blood. 2018 Jun 21;131(25):2826-2835. doi: 10.1182/blood-2017-09-804666. Epub 2018 Mar 28. PMID: 29592891; PMCID: PMC6014353. https://pmc.ncbi.nlm.nih.gov/articles/PMC6014353/

(Watzka, et al., 2014) Watzka M, Geisen C, Scheer M, Wieland R, Wiegering V, Dörner T, Laws HJ, Gümrük F, Hanalioglu S, Unal S, Albayrak D, Oldenburg J. Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations. Thromb Res. 2014 Oct;134(4):856-65. doi: 10.1016/j.thromres.2014.07.004. Epub 2014 Jul 12. PMID: 25151188. https://pubmed.ncbi.nlm.nih.gov/25151188/