Untangling Cardiovascular Disease, Part 5

All About Nattokinase

This entire series of cardiovascular articles is dedicated to my brother Jeff, may he rest in peace. He died from a heart attack on July 4th, 2020, at only 59 years old. Below is a picture of him so you can get a glimpse into my motivation for researching and writing this series.

*Apologies for the delay in getting this out to you. I’ve had some health challenges recently, from which I’ve learned a lot and can’t wait to share it with you in future articles. True to brand, I’ve been trying to figure out medical puzzles the hard way.*

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Sticky Like Glue, Slimy Like a Boogie, Happy as a Clam

In Part 1 and Part 2 of this series, I wrote about how I started down this cardiovascular rabbit hole: With the infamously slimy, sticky, and smelly natto, arguably one of the most repulsive but healthiest foods on the planet. In trying to understand its secrets, I began with the obvious—Natto is by leaps and bounds the single most potent dietary source of vitamin K2-7.

When researching the earlier parts of this series, I experienced a full-on vitamin K epiphany, but it left me with mixed feelings. At first, I was thrilled—Reverent wonder at the remarkable breadth and strength of the published medical literature demonstrating how vitamin K helps prevent cardiovascular disease and bone loss. But then came the bitter aftertaste—The frustration that the vast majority of this data hasn’t trickled down to physicians and patients. And what’s a wound without a little salt—It may never trickle down.

There’s just no money to be made by pharma from vitamin K. And there’s the rub that keeps on rubbing. The recurring miserable theme—Pharma is steering mainstream medicine’s boat. It’s been because of this that for decades medical science has been strolling along at a slow trot rather than a full sprint.

But as exceptional as vitamin K2-7 is, up there in my book with monolaurin, it’s not the only ingredient in natto with powerful bioactive properties.

Nattokinase

In the vast entirety of nature, nattokinase is found primarily in natto, the diminutive Japanese breakfast superfood. Recognized for its potential cardiovascular benefits, nattokinase is now a popular over-the-counter supplement, but does it work? If so, how does it work? And is it safe?

Of its several mechanisms of action, arguably its most important is its ability to dissolve blood clots, which could be helpful when it comes to the prevention of cardiovascular disease—But could that also raise the risk of serious bleeding as a side effect? The short answer is yes, but short answers in medicine lack nuance—And medicine is about not only facts, but perspective—So please read the entire article to get the bigger picture.

The Clot Thickens

That blot clotting itself may be a foundational cause of cardiovascular disease, rather than simply an effect, is explored in the thought-provoking book The Clot Thickens. The author takes a contrarian view, turning away from the prevailing cholesterol as cause dogma. Is there validity to his position? And if so, could anti-clotting therapy be helpful?

A controversy is almost always worth investigating because by its very existence, it must mean that there is at least a kernel of truth at its core. If there was absolutely no truth to a matter, then there’d be no controversy. It would be a ho-hum, boring, slam dunk no, and that would be it. The truth of most controversies often lies upon the middle ground—Hidden from sight by the biases of those who view the issue from either side.

So, consistent with viewing clotting as a central theme of cardiovascular disease, let’s explore how nattokinase may have activity: It directly breaks down fibrin. An insoluble protein made in response to bleeding and/or tissue damage, fibrin is the major component of blood clots. In addition to that direct activity, nattokinase also increases levels of our own clot dissolving chemicals, such as our tiny amounts of naturally occuring tissue plasminogen activator (tPA), which has been made into an FDA-approved clot-dissolving drug.

The workhorse of thrombolytic treatments, tPA has been used for heart attacks, clotting strokes, and pulmonary emboli. The mechanism of action is by increasing plasmin, which then dissolves clots. I’m a fan of tPA, having personally seen it save many lives, but it can also cause dangerous, sometimes fatal, bleeding. Wouldn’t it be great to have something that works comparably to tPA, but with a better safety margin?

Nattokinase vs tPA

A rat study was done to delineate the effects of tPA vs nattokinase on clot dissolving, from the dual-perspective of efficacy and bleeding risk:

“Anti-thrombotic activity and safety of nattokinase…were investigated in comparison with tissue-type plasminogen activator (t-PA). Carotid arterial thrombosis was produced…followed by intravenous injection of nattokinase or t-PA. Nattokinase and t-PA delayed thrombus formation, near-fully (> 90%) inhibiting at 75 and 8.5 mg/kg, respectively. As adverse effects, t-PA induced petechial haemorrhage at 10 mg/kg in the lungs and thymus, and extensive bleeding at 20 mg/kg. Nattokinase also caused pulmonary haemorrhage from 300 mg/kg. Collectively, the standard safety margins (SSMs) for t-PA and nattokinase were calculated to be 1.2 and 4.0, respectively….The results indicate that nattokinase delayed thrombus formation and dissolved thrombi, and that nattokinase could be a good candidate anti-thrombotic agent with relatively-low haemorrhagic risk.”

This means that both nattokinase and tPA comparably reduced blood clotting at their respective effective doses, but that nattokinase caused bleeding at 4 times its effective dose, whereas tPA caused bleeding at only 1.2 times its effective dose. The range in which a medicine can be both effective but still remain generally safe is called its therapeutic window. And in this case, bigger is better—It demonstrates that nattokinase has a superior margin of safety for bleeding risks, but that these risks are still material if the dose is high enough.

Our FDA-approved pharmaceutical blood thinners raise the risk of serious bleeding. Doctors prescribe them when it’s felt that the potential benefits outweigh the potential risks, but we’re in need of products that are safer without compromising efficacy. So given the animal daata, why aren’t there randomized controlled human trials in humans using nattokinase vs tPA for heart attacks, clotting strokes, and pulmonary emboli? Could it be that there’s no money in it for pharma?

And just in case someone misinterprets what I'm writing—I am in no way advocating for taking nattokinase instead of tPA for a heart attack, stroke, or pulmonary embolism. But I am advocating for human trials to clarify if there are safer, and/or more effective, thrombolytic options to improve the standard of care for cardiovascular disease.

Nattokinase vs Natto

As discussed in Part 1, in a study of almost 30,000 people, those who ate the most natto had 25% less deaths from any cardiovascular disease and 33% less deaths from clotting strokes compared to those who ate the least natto. But an important observation from that same study is that those who ate the most natto did not have an increase in bleeding strokes, which gives insight into its safety profile, at least at the dose of nattokinase in natto.

A typical serving of natto has about 100 mg of nattokinase, which is about 2000 fibrinolytic units (FU’s). It’s annoying, but some studies list nattokinase in mg’s and in other studies it’s listed as FU’s.

A single nattokinase dose of 2000 FU’s is enough to significantly impact multiple clotting parameters via different mechanisms, but not enough to take them out of the normal range:

“A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK… or placebo…D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range…a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.”

Is this small dose of nattokinase enough on its own to improve cardiovascular risks? Or does it only work in natto because of synergy with natto’s high dose of vitamin K2-7? Or is it due to synergy with its other ingredients?

Natto contains many other bioactive compounds besides nattokinase. Apart from the obvious vitamin K2-7, another significant component of natto includes soy isoflavones, which have been shown to improve cholesterol in a meta-analysis of eight studies, among their other potential benefits.

So to evaluate the effects of nattokinase on its own, we have to look at supplementation studies of just that one component.

The Good

Nattokinase appears to have a low risk for toxicity:

“Nattokinase was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 28-day and 90-day subchronic toxicity studies conducted in Sprague-Dawley rats at doses up to 167 mg/kg-day and 1000 mg/kg-day, respectively…Additionally consumption of 10 mg/kg-day nattokinase for 4 weeks was well tolerated in healthy human volunteers. These findings suggest that the oral consumption of nattokinase is of low toxicological concern.

This means that in animal studies there was no evidence found for the potential for nattokinase to cause cancer and that very high doses were well-tolerated for up to 90 days. And in humans, a high dose, for example, for a 150 lb person, equal to 680 mg (13,600 FU’s) per day, was well-tolerated for 4 weeks.

To initially evaluate safety and efficacy against cardiovascular disease in humans, a randomized controlled trial of 76 patients was performed. Nattokinase at 6000 FU’s per day demonstrated both lipid lowering efficacy and protection against carotid artery atherosclerosis. The activity of nattokinase was compared to simvastatin, a cholesterol lowering medication, over 6 months:

“…patients were randomly assigned to one of two groups, NK [nattokinase] and Statin (ST) group…NK at a daily dose of 6000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks…there was a significant reduction in CCA-IMT [carotid artery intima-media thickness, a marker of early carotid artery disease] and carotid plaque size in both groups…The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group). Both treatments reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG)…the reduction of TC, LDL-C and TG in ST group was significantly greater (P<0.05). In addition, NK significantly increased the level of high-density lipoprotein cholesterol (HDL-C) (P<0.05), in contrast, HDL-C in the ST group did not change…NK supplementation is an effective way to manage the progression of atherosclerosis and potentially may be a better alternative to statins…The mechanism underlying the reduction of carotid atherosclerosis by NK may be independent from its lipid-lowering effect, which is different from that of statins.”

Although simvastatin was more effective at lowering cholesterol, nattokinase was more protective against carotid artery vascular disease, implying other actionable strategies against atherosclerosis, apart from lowering cholesterol.

In a much larger study by some of the same researchers along with others— This time 1,062 patients were evaluated over a year—They explored the safety and efficacy of an even higher dose of nattokinase, and compared it to the efficacy of lower doses:

“…clinical study involving 1,062 participants, our objective was to examine the efficacy of NK in atherosclerosis and hyperlipidemia and safety at the dose of 10,800 FU/day after 12 months of oral administration…at a dose of 10,800 FU/day effectively managed the progression of atherosclerosis and hyperlipidemia with a significant improvement in the lipid profile. A significant reduction in the thickness of the carotid artery intima-media and the size of the carotid plaque was observed. The improvement rates ranged from 66.5 to 95.4%. NK was found to be ineffective in lowering lipids and suppressing atherosclerosis progression at a dose of 3,600 FU/day. The lipid-lowering effect of NK was more prominent in subjects who smoked, drank alcohol, and subjects with higher BMI. Regular exercise further improved the effects of NK. Co-administration of vitamin K2 and aspirin with NK produced a synergetic effect. No noticeable adverse effects associated with the use of NK were recorded. In conclusion, our data demonstrate that atherosclerosis progression and hyperlipidemia can be effectively managed with NK at a dose of 10,800 FU/day. The lower dose of 3,600 FU per day is ineffective. The dose of 10,800 FU/day is safe and well tolerated…Our findings provide clinical evidence on the effective dose of NK in the management of cardiovascular disease and challenge the recommended dose of 2,000 FU per day.

Notable findings of this study include the efficacy of higher dose, but not lower dose nattokinase, in reducing carotid artery vascular disease and lowering lipids, along with the absence of adverse events. Increased effects from nattokinase were found when used in combination with other interventions, such as exercise and vitamin K2. (They didn’t specify if it was K2-7, but it appears to be so because the dose was 180 mcg/day, which is a common K2-7 dose. And when I looked up the manufacturer listed in the study, they make K2-7 in that dose, so I’m going to assume it’s K2-7 going forward.) Although they found additional improvements with aspirin as well, I think that more safety data beyond this study would be required in order to evaluate this combination from both a synergy and a bleeding risk perspective, as less than 10% of the participants were on both aspirin and nattokinase.

What was not evaluated—But what I think is extremely important—Would have been to further clarify the potential for synergy between vitamin K2-7 and nattokinase. Could it be that with enough vitamin K2-7, low dose nattokinase would be more effective?

Less than 20% of the patients in the study took vitamin K2-7, and the dose was only 180 mcg per day. A single serving of natto has 900 mcg of vitamin K2-7 and 100mg/2000 FU’s of nattokinase. Since we know that people who regularly eat natto have wonderful cardiovascular health statistics, they should have studied the amounts of vitamin K2-7 and nattokinase contained in a daily serving of natto—To see if the benefits could be reproduced in pill form, without the slimy yuk-factor.

Less impressive than the above-listed studies are the results of a meta-analysis of six randomized controlled trials which evaluated for a variety of cardiovascular risks, but which did not include direct measures of atherosclerosis. This meta-analysis demonstrated that nattokinase improved high blood pressure, while its effect on lipids were inconclusive—But it consisted of primarily low dose nattokinase trials. Despite this, there was still a trend toward lowering lipids at higher doses. There were no adverse events reported.

The Bad

In this randomized controlled trial of nattokinase 2000 FU’s over 3 years , it failed to reduce carotid artery intimal thickening.

“In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis…CONCLUSIONS:Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.”

This is compatible with the other above-referenced data demonstrating that low dose nattokinase on its own is ineffective.

The Ugly

Can bleeding side effects from nattokinase occur? Yes.

Although the consumption of natto has not been associated with bleeding risks in large epidemiologic studies, there have been at least 2 published cases that I could find of serious, even fatal, human bleeding in patients taking higher doses of nattokinase.

In one case, a 52-year-old woman with a history of high blood pressure, prior clotting stroke, and cerebral small vessel disease on a prior CT brain, developed a cerebral hemorrhage a week after starting nattokinase 400 mg (8000 FU’s) per day, in addition to low-dose aspirin she’d already been taking. It’s noteworthy to point out that her father and one of her paternal uncles had a history of multiple cerebral hemorrhages with ultimate fatality.

In a 2nd case, a 92-year-old female presented to the hospital for a fall, with resultant fatal internal bleeding into her abdomen. She wasn’t on prescription anticoagulants or aspirin, but she did take nattokinase, dose unknown. The article states:

“She is unsure how many she takes, “sometimes a handful”. She lived alone and as such there was no one to confirm how many nattokinase supplements she had been taking daily.”

So bleeding on nattokinase can definitely occur, but in each of these cases it appears to have been associated with higher doses and special circumstances.

In the first case, nattokinase was combined with low dose aspirin. The use of daily low dose aspirin on its own increases the risk of cerebral bleeding by 38%. And that patient had both a strong family history of intracranial bleeding along with a personal history of cerebrovascular disease.

The second case is also imbued with murkiness. To start, the nattokinase dose—A “handful” is an unknown with significant variability. They also didn’t provide the weight of the patient. Since frailty is common among 92 year old women, the chance of the patient being of lower body weight is significant— Medication and/or supplement doses must take body weight into account. And the elderly are at higher fall risk and thus may be prone to serious injury from blunt abdominal trauma.

Benefits, Beyond the Expected

Nattokinase promotes neurogenesis, which has potential ramifications for a range of neurologic disorders—The regrowth of nerve cells are notoriously difficult to do in the brain and spinal cord.

“The therapeutic potential of treatments for post-stroke cognitive impairment (PSCI) is severely limited by the autonomic regeneration capacity of the adult brain…Our study demonstrates that NK protects against acute ischemic stroke and impressively promotes neurogenesis in rat models by increasing peripheral blood irisin, leading to improved cognitive functions. Our findings demonstrate NK to be a promising candidate for treating PSCI, and we also highlight irisin as a novel target of NK…”

Another category of diseases for which neurogenesis is vital, are the neurodegenerative illnesses, of which Alzheimer’s dementia is one. These are complex and heterogeneous pathologies, but there are common threads that tie them together, one of them being infections.

Amyloid, the aberrant protein associated with Alzheimer’s, serves a defensive role as an antimicrobial peptide, protecting us from a host of infections. But amyloid damages the body as part of a longer term process. In a perfect world, its triggering would be limited during infection, and avoided in the absence of infection.

But it’s not a perfect world. Diseases due to amyloid have been documented after both Covid and Covid vaccination—And biochemical mechanisms have been established for the proliferation of amyloid by both. Nattokinase degrades amyloid in the test tube as well as in an animal model.

Staying on the topic of Covid, its spike protein, whether due to Covid infection or vaccination, can cause disease in a variety of ways, independent of active Covid infection. And nattokinase degrades Covid spike protein as well.

The Verdict

I think there's enough evidence to support the potential for nattokinase to contribute to a broad range of health benefits. But on its own, nattokinase does not appear to be a miracle intervention—I've stopped believing in those a long time ago—And it’s not without the potential for bleeding risks.

But neither is taking an aspirin, so please check with your doctor before undertaking any course of action.

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Disclaimer: None of my posts, articles, podcasts, or any public communications contain medical advice. These are intended for purely informational purposes only. Please check with your doctor before undertaking any course of treatment.

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