What is nattokinase

Nattokinase is a potent blood-clot dissolving protein (fibrinolytic or antithrombotic serine protease) with a potent fibrin-degrading activity (breaks down fibrin blood clot) ¹. Nattokinase can break down blood clots by directly hydrolyzing fibrin and plasmin substrate, converts endogenous prourokinase to urokinase (uPA), degrades PAI-1 (plasminogen activator inhibitor-1) and increases tissue plasminogen activator (t-PA) which supports fibrinolytic activity (Figures 2 and 3)  ². Unlike common fibrinolytic enzymes, such as tissue plasminogen activator (t-PA), urokinase (uPA) and streprokinase, which can produce various side effects such as bleeding, nattokinase exhibits little to no side effects ³, low cost and long life-time, and it has the potential to be used as a drug for treating cardiovascular disease and served as a functional food additive ⁴. Studies also indicate that an oral administration of nattokinase can be absorbed by the intestinal tract ⁵. Nattokinase exhibits strong fibrinolytic activity after intraduodenal absorption. These characteristics make nattokinase a versatile and potent fibrinolytic enzyme that can be used to combat blood clots. At present, commercial nattokinase products are widely-used in Japan, China, Korea, Australia, European Union Countries, Canada, and the United States as a food supplement to thin blood, prevent blood clots, and improve blood circulation. The cost of nattokinase supplements is relatively inexpensive, with the cost of daily doses of 200 to 400 mg being approximately US $0.3 to US $0.8 depending on the source of the product ⁶.

Nattokinase supplementation has shown to enhance markers of fibrinolysis and anticoagulation and to decrease blood pressure and atherosclerosis in human subjects ⁷. In addition, in both animal and human studies, nattokinase also has an antihypertensive ⁸, anti-atherosclerotic ⁹, lipid-lowering ⁹, antiplatelet or anticoagulant ¹⁰ and neuroprotective actions ¹¹. All these pharmacologic actions of nattokinase have relevance to the prevention and treatment of cardiovascular disease ⁷. It therefore has the potential to be developed as a new-generation drug for the prevention, treatment, and long-term care of cardiovascular disease ⁸. Furthermore, nattokinase is a natural product that can be administered orally, has a proven safety profile, is economical to use, and provides distinct advantages over other pharmaceutical products ⁷.

Nattokinase is produced by the bacterium Bacillus subtilis during the fermentation of soybeans to produce Natto, a fermented soybean product that has been consumed as a traditional food in Japan ³. Natto is regarded as a fibrinolytic miracle food. In 1980, Hiroyuki Sumi, a Japanese researcher at the Chicago University Medical School, discovered that natto can dissolve artificial fibrin ¹². Sumi and his team ¹² extracted an enzyme from natto that not only degraded fibrin but also a plasmin substrate. He named this novel, fibrinolytic enzyme “nattokinase”.

One key question that has not been adequately addressed is the mechanism by which nattokinase is absorbed into the bloodstream after oral administration ⁷. There is no current convincing data available to demonstrate the bioavailability and metabolism of nattokinase administered as an oral dose. The only related study is one showing that, in rats, intraduodenal administration of nattokinase, at a dose of 80 mg/kg leads to degradation of fibrinogen in plasma ¹³. It should be noted that the nattokinase used was not subjected to digestive gastric fluids and the dose was high in pharmacologic terms. Thus, the relevance of the data is questionable. Recent pilot studies on the pharmacokinetics of nattokinase have not provided an answer to the question of how nattokinase is absorbed into the body ¹⁴. The pharmacokinetic data are rather inconsistent and mismatched with pharmacodynamic activities. Ero et al ¹⁴ claimed that nattokinase was measured directly in their study with a peak concentration at 13.3 hours after oral administration, whereas the thrombolytic activity of nattokinase, measured in another study, was shown to peak 2 to 4 hours after oral dosing ¹⁵. These data imply that measurements of nattokinase in the published studies may not be those of the intact nattokinase molecule. Although it has been assumed that nattokinase is stable in the gastrointestinal tract ⁶, it is important to address the key question of the mechanism of nattokinase absorption into the body, with more convincing direct evidence. In fact, several groups have pointed out that the molecular size of nattokinase is considered to be generally too large for oral absorption through the gastrointestinal tract ¹⁶. It is recognised that nattokinase may be susceptible to chemical oxidation and subsequent inactivation, or denaturation, in the gastrointestinal tract ¹⁷. Thus, further studies are required to fully understand the pharmacokinetics of nattokinase.

Figure 1. Nattokinase chemical structure

Figure 2. Nattokinase mechanism of action

Footnotes: Nattokinase dissolves blood clots by directly hydrolyzing fibrin and plasmin substrate. It converts endogenous prourokinase to urokinase (uPA). It also degrades plasminogen activator inhibitor (PAI-1) and increases the level of tissue plasminogen activator (t-PA).

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Figure 3. Nattokinase benefits

Footnote: Pharmacologic actions of nattokinase as related to cardiovascular health and disease.

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Nattokinase and serrapeptase

Serracor-NK (AST Enzymes) is an over-the-counter (OTC) supplement that consists of enteric-coated serrapeptase and nattokinase in a capsule form ¹⁸. Serrapeptase also known as serratiopeptidase, is a proteolytic enzyme, derived from the Serratia bacterium, with anti-inflammatory, anti-edemic and analgesic ¹⁹. Enteric coated oral formulation of serrapeptase (serratiopeptidase) enzyme is being used commonly in various specialities like surgery, orthopaedics, otolaryngology, gynecology and dentistry for its anti-inflammatory and anti-edemic properties ¹⁹.

Serrapeptase (serratiopeptidase) is thought to work in three ways:

1. Anti-inflammatory: Serrapeptase (serratiopeptidase) reduces swelling by the process of decreasing the amount of fluid in the tissues, thinning the fluid, and by facilitating the drainage of fluid. In addition, its enzyme activity dissolves dead tissue surrounding the injured area so that healing is accelerated ²⁰. Serrapeptase (serratiopeptidase) may also act by modifying cell-surface adhesion molecules that guide inflammatory cells to their target site of inflammation. These adhesion molecules play an important role in the development of arthritis and other autoimmune diseases ²¹.
2. Analgesic: Serrapeptase (serratiopeptidase) may help alleviate pain by inhibiting the release of pain-inducing amines like bradykinin from inflamed tissues ²².
3. Fibrinolytic/caseinolytic: Serrapeptase (serratiopeptidase) may be beneficial in atherosclerotic disease as it acts by breaking down fibrin and other dead or damaged tissue without harming living tissue. This could enable the dissolution of blood clots, and atherosclerotic plaques ²³.

Serrapeptase is even being promoted as a health supplement to prevent cardiovascular morbidity. The existing scientific evidence for serrapeptase (serratiopeptidase) is insufficient to support its use as an analgesic and health supplement ¹⁹. Several small serrapeptase (serratiopeptidase) clinical trials from the orthopedic, otorhinolaryngology, and dentistry literature have suggested improvements in pain and inflammation for conditions such as carpal tunnel syndrome, arthritis, and molar extraction. Although reports detailing adverse effects with serrapeptase (serratiopeptidase) are few, pneumonitis, joint aches, and dermatitis have all been reported with the oral preparation ¹⁹.  The data on long-term safety of serrapeptase (serratiopeptidase) is lacking. Evidence based recommendations on the analgesic, anti-atherosclerotic efficacy, safety and tolerability of serrapeptase (serratiopeptidase) are needed ¹⁹.

There are not many published reports of Adverse Drug Reactions serrapeptase (serratiopeptidase) ¹⁹. The only information available is drug companies monographs. The serrapeptase (serratiopeptidase) side effects include allergic skin reactions which could range from dermatitis to extreme cases of Stevens–Johnson syndrome or erythema multiforme, muscle aches and joint pains, gastric disturbances like anorexia, nausea and abdominal upset, cough rarely pneumonitis ²⁴ and coagulation abnormalities.

The enzyme activity is measured in units. Serrapeptase (serratiopeptidase) 10 mg is equal to 20,000 units of enzyme activity.

The serrapeptase (serratiopeptidase) dose which has been used in clinical studies and mentioned in drug monographs ranges from 10 mg to 60 mg per day. Serrapeptase (serratiopeptidase) has to be taken on an empty stomach or at least two hours after eating, and no food should be consumed for about half an hour after taking Serratiopeptidase. The recommended dose of serrapeptase (serratiopeptidase) for specific indications, in particular is not mentioned anywhere.

Nattokinase, a protease with fibrinolytic activity, was derived from Bacillus subtilis ¹². Nattokinase is being investigated as an alternative to currently available thrombolytic agents and has been suggested to protect the brain in the setting of an ischemic insult ²⁵. Interestingly, the 2 agents, serrapeptase and nattokinase, together have been studied in a rat model for Alzheimer’s disease ²⁶.

Nattokinase food sources

The fermented soybean product, natto, is the main source for obtaining purified nattokinase ³. A similar enzyme has been extracted from other fermented soybean-based foods, such as Thai thua nao ²⁷, Chinese douchi ²⁸ and Korean doen-jang ²⁹.

The mild odor and stringy texture of natto is a major drawback to its use as a common food. Outside of Japan, nattokinase is generally consumed orally in capsules typically made of vegetable-based materials for vegetarians. The presence of impurities in current nattokinase products, however, prevents their common use as therapeutic medicine for thrombosis. Current nattokinase products have raised concerns in the Federal Drug Administration (FDA) due to the requirement of high-levels of purity in single component entities. Thus, recombinant technologies have been explored to increase the quantities and purity of the nattokinase being produced.

The traditional process of fermenting soybeans to make natto is simple and straightforward, and can be easily done at home. Bacillus subtilis (natto) is the starter used to make natto, commercially and at home. Bacillus subtilis (natto) can maintain activity at a pH of 6–12 and resist high temperatures up to 60 °C ³⁰. The Bacillus subtilis strains present in current commercial nattokinase products can maintain viability and metabolic activity at room temperature for at least six months. Cooked soybeans are inoculated with Bacillus subtilis (natto) and incubated at room temperature to ferment for at least 24 hours until the beans are covered with a viscous and sticky substance produced by the bacterium and consisting of glutamic acid polymers. Commercial nattokinase production practices optimize the fermentation conditions to maximize the yield of nattokinase produced by Bacillus subtilis (natto), and include optimal temperature, pH, and fermentation time ³¹. A variety of nutrients, such as glycerol, yeast extract, soy peptone, or shrimp shell powder have been examined for their ability to increase nattokinase yield ³². The optimal feed strategy used in in fed-batch fermentation methods has significantly enhanced nattokinase production, relative to yields obtained by batch fermentation ³³.

Compared to the simple fermentation process, downstream extraction and purification of nattokinase from natto slurry is difficult and inefficient. Several steps are required, including homogenization with an organic solvent, salting out the proteins, protein ion-exchange chromatography and dialysis, etc. Low nattokinase activity recovery from these involved processes have driven researchers to investigate more inexpensive, rapid, and efficient techniques for nattokinase purification ³⁴. Garg and Thorat ³⁵ developed a three phase partitioning technique to purify nattokinase by combining t-butanol (1.5× to crude extract) and ammonium sulphate (30% w/v) to precipitate the nattokinase protein. The desired results were obtained using an optimal pH (8.0) and temperature (37 °C). nattokinase activity varies, however, when different purification methods are used. In addition, there is also potential for the retention of excessive byproducts in the final product than can cause an allergenic reaction ³⁶.

Nattokinase benefits

Nattokinase is considered to be a safe, powerful, low cost, and all-natural supplement for the treatment of heart and cardiovascular disease ³⁷. Animal ⁵ and human trials ³⁸ have demonstrated that nattokinase provides support to the circulatory system by thinning the blood and dissolving blood clots. When dogs were orally administered four nattokinase capsules (2000 fibrinolytic units/capsule), chemically-induced thrombi in the major leg vein were completely dissolved within five hours and normal blood flood was restored ³⁹. A rat model of thrombosis in the common carotid artery also demonstrated that nattokinase-treated rats recovered 62% of arterial blood flow. Nattokinase exhibited considerably stronger thrombolytic activity than the fibrinogenolytic and fibrinolytic enzymes, plasmin, or elastase; which restored 15% and 0% of blood blow in the rat carotid artery, respectively ⁴⁰.

Nattokinase was reported to have an effect on both oxidative injury-mediated arterial thrombosis ⁴¹ and inflammation-induced venal thrombosis ⁴². When ferric chloride (FeCl3) was administered to the injured arteries, it resulted in oxidative thrombosis and platelet adhesion. After treatment with nattokinase, however, thrombus formation and platelet aggregation were inhibited. The effects of nattokinase are similar to the well-known blood thinner, aspirin ⁴¹. Unlike aspirin, which often triggers bleeding or gastric ulcers, nattokinase improves blood flow without any adverse effects. Carrageenan induced inflammatory thrombi formation in rat tails was used to examine the effect of nattokinase ⁴². Twelve hours after gavage administration of nattokinase, higher levels of fibrin degradation product fragments and d-dimers were detected in blood samples. A greater than 50% decrease in thrombosis was observed in the blood vessels of the rat tail by biopsy analysis.

Elevated levels of factor VII and VIII are associated with greater risk of cardiovascular disease due to the potential of these factors to trigger a blood coagulation cascade. In a human trial, three groups (healthy volunteers, patients with cardiovascular risk factors, and patients undergoing dialysis) were orally administered two capsules of nattokinase (2000 fibrinolytic units/capsule) on a daily basis. After two months, a significant and similar decrease in factor VII, factor VIII, and fibrinogen was observed in all of the groups. No adverse effects were detected during the two-month trial and heart rate, body weight, and uric acid levels remained stable ⁴³.

Nattokinase has a strong ability to breakdown thrombi and fibrin. Even a single dose of nattokinase has been reported to result in fibrinolysis via the cleavage of cross-linked fibrin ⁴⁴. In that study, 12 healthy, young males were randomly administered a single capsule of nattokinase (2000 fibrinolytic units) ⁴⁴. The antithrombin concentration in their blood increased significantly two hours after the oral consumption of the nattokinase capsule. Fibrin degradation product fragments and D-dimers were observed four and six hours after nattokinase administration, respectively, and factor VIII activity declined four hours after nattokinase ingestion. The results of this study indicated that multiple different pathways may be involved in nattokinase fibrinolysis and anti-coagulation activity.

Both nattokinase and lumbrokinase (derived from earthworms), unlike most proteins, are more resistant to the highly acidic gastric fluids in the stomach and can be absorbed in the later sections of the digestive tract. In 1995, Fujita and colleagues ⁴⁰ demonstrated that nattokinase could be absorbed from the rat intestinal tract in an intact form and degraded fibrinogen in plasma blood samples. Subsequently, in 2013, a research team in the United States detected intact nattokinase in the serum of healthy humans after they were administrated a single, oral dose of nattokinase (2000 fibrinolytic units/100 mg) in a capsule ⁴⁵. Other studies have also shown that oral administration of nattokinase can enhance fibrinolytic activity in plasma. The mechanism by which nattokinase is transported from the digestive tract into the circulatory system still needs to be elucidated. nattokinase can resist high temperature (50 °C) and pH (to 10), which certainly contributes to the ability of this enzyme to remain intact in the gastrointestinal tract ⁴⁶.

Studies also indicate that nattokinase can ameliorate other diseases such as hypertension ⁵, stroke ⁴⁷, Alzheimer’s disease ⁴⁸ and atherosclerosis ⁴⁹. The potential of using nattokinase to decrease atherothrombotic risk and slow the progression of atherosclerosis as well as cognitive decline is currently being assessed in a Phase II clinical trial ⁵⁰.

Although nattokinase has recently gained popularity as a candidate drug for cardiovascular disease, clinical investigations of nattokinase in humans are relatively limited. The first nattokinase clinical study conducted in 1990 aimed to assess its fibrinolytic activity in healthy subjects after oral administration ⁵¹. A further Japanese study ⁵² examined the efficacy of nattokinase in the prevention of stroke progression in patients with acute ischemic stroke and showed clear beneficial effects in these patients after oral administration. As shown in Table 1, there are no more than 10 published clinical studies covering the use of nattokinase or the natto extract. Other related nattokinase clinical studies include investigations of antihypertensive effects in patients in North America ⁵³ and Asia ⁵⁴. Further studies also include anti-atherosclerotic ⁹ and lipid-lowering effects ⁵⁵, fibrinolytic activity and effects on coagulation ⁵⁶ and pharmacokinetics ¹⁴ and toxicology ⁵⁷ in humans. The low number of nattokinase clinical studies is probably related to the fact that nattokinase is not registered as a drug, but, as a nutritional supplement, and, to date, clinical evidence has not been adequately conclusive.

Table 1. List of published clinical studies on nattokinase

Year	Location of study	Size of study	Clinical condition observed	Summary of findings	References
1990	Japan	12	Fibrinolytic activity	3× nattokinase daily oral administration resulted in enhanced fibrinolytic activity in the plasma and production of tissue plasminogen activator	Sumi et al 51
2004	Japan	24	Ischaemic stroke	Nattokinase demonstrated a clear neuroprotective effect in patients with acute ischaemic stroke	Shah et al 52
2008	Korea	86	High blood pressure (hypertension)	Nattokinase supplementation resulted in a reduction in both systolic and diastolic blood pressure	Kim et al 54
2009	Taiwan	45	Blood coagulation factors	2 months of nattokinase treatment significantly decreased fibrinogen, factor VII, and factor confirming a promising cardiovascular benefit	Hsia et al 58
2009	Taiwan	30	Hyperglycemia (high blood sugar)	A decrease in serum cholesterol, LDL-C (low density lipoprotein or “bad” cholesterol), and HDL-C (high density lipoprotein or “good” cholesterol) in the nattokinase group was observed following 8 weeks of treatment (4000 fibrinolytic units), but the difference was not statistically significant	Wu et al 55
2013	USA	11	Pharmacokinetics	Nattokinase can be measured directly in the human blood after single dosing. Serum levels of nattokinase peaked at approximately 13.3 hours ± 2.5 hours	Ero et al 14
2015	Japan	12	Thrombolysis and anticoagulation	Blood fibrin/fibrinogen degradation products (thrombolysis and anticoagulation profile) were significantly increased 4 hours after nattokinase administration following a single dose of 2000 fibrinolytic units, supporting nattokinase as a useful fibrinolytic/anticoagulant agent to reduce the risk of thrombosis and cardiovascular diseases in humans	Kurosawa et al 15
2016	USA	79	Hypertension and von Willebrand factor (vWF)	Nattokinase consumption for 8 weeks led to beneficial changes to blood pressure in hypertensive patients. A decrease in von Willebrand factor (vWF) was seen in the female population consuming nattokinase	Jensen et al 53
2016	USA	11	Toxicology/toxicity	Nattokinase consumption of 10 mg/kg/day for 4 weeks was well tolerated in healthy human volunteers suggesting that the oral consumption of nattokinase is of low toxicological concern	Lampe and English 57
2017	China	76	Atherosclerosis and hyperglycaemia	Daily nattokinase treatment (6500 fibrinolytic units for 26 weeks) effectively suppressed the progression of atherosclerosis in patients with atherosclerotic plaques by reducing common carotid artery-intima-media thickness and carotid plaque size significantly. Nattokinase treatment reduced total cholesterol, LDL-C (low density lipoprotein or “bad” cholesterol), triglyceride and increased HDL-C (high density lipoprotein or “good” cholesterol) in hyperlipidemic patients	Ren et al 9

Nattokinase and blood clots

Since nattokinase discovery in 1987, multiple laboratory and human studies have consistently reported the potent fibrinolytic and antithrombotic action of nattokinase ⁵⁹. A considerable amount of work has been performed to evaluate the thrombolytic effects of nattokinase in vitro and in animal models. Using a rat model, Fujita et al ⁶⁰ examined the effect of nattokinase on chemically induced thrombi in the common carotid artery and found nattokinase to be 4 times more potent than plasmin in thrombus dissolution. At a concentration of 2836 fibrinolytic units, nattokinase lysed 88% of thrombi within 6 hours ⁶¹ and nattokinase exhibited significant prophylactic antithrombotic effects in vivo. The efficacy of nattokinase against thrombosis was confirmed in a carrageenan-induced tail thrombosis model ⁶². The survival rate of mice with pulmonary thrombosis was increased by nattokinase and the formation of thrombosis in mice was remarkably inhibited by nattokinase, demonstrating significant antithrombotic effects ⁶³. In addition, in a model of rat experimental pulmonary thrombosis, oral administration of nattokinase led to a decrease in thrombus count and plasma euglobulin lysis time, as well as an increase in tissue plasminogen activator (tPA), indicating that nattokinase is capable of activating plasma fibrinolysis in vivo ⁶⁴. Omura et al ⁶⁵ further found that a purified protein layer, NKCP, which mainly consisted of nattokinase, had both fibrinolytic and antithrombotic effects, which they described as being similar to that of heparin. In rats, Natto treatment shortened euglobulin lysis time and significantly prolonged partial thromboplastin time compared with a nontreated rat group ⁶⁶.

It is now known that nattokinase not only degrades fibrin directly and effectively but also increases the release of tPA with a subsequent increase in the formation of plasmin ³. Plasminogen activator inhibitor 1 (PAI-1) is the primary inhibitor of tPA and regulates fibrinolytic activity in the fibrinolytic cascade ⁶⁷. In a study investigating the mechanism by which nattokinase exerted its fibrinolytic effect, nattokinase enhanced fibrinolysis through cleavage and inactivation of PAI-1 ¹. In this study ¹, nattokinase was shown to cleave active recombinant prokaryotic PAI-1 into low-molecular-weight fragments as well as enhance tissue-type plasminogen activator–induced fibrin clot lysis. The enhanced fibrinolytic activity observed in the absence of PAI-1 appeared to be induced through direct fibrin dissolution by nattokinase ¹. Nattokinase also enhanced the production of clot-dissolving agents such as urokinase through the conversion of prourokinase to urokinase ¹⁶. Furthermore, nattokinase was shown to be capable of blocking thromboxane formation resulting in an inhibition of platelet aggregation without producing the side effect of bleeding ¹⁰. Thus, nattokinase was found to be a potent antithrombotic agent, and by reducing thrombus formation, was able to slow the progression of plaque formation and reverse evolving atherosclerotic lesions ⁶⁸.

Data from human studies also strongly support nattokinase or natto as a potent and promising fibrinolytic agent. In an early human trial, oral administration of nattokinase was shown to produce a gradual enhancement of fibrinolytic activity in the plasma, as indicated by plasma euglobulin lysis time and the production of tPA ⁶⁹. Following administration of natto bacillus (100 mg/kg) to healthy adult volunteers, euglobulin lysis time was reduced and tPA activity was increased significantly ⁶⁴. In an open-label, self-controlled clinical trial, Hsia et al ⁵⁸ found that after 2 months of administration, fibrinogen, factor VII, and factor VIII levels were decreased significantly implying a promising cardiovascular benefit from nattokinase administration. Even after a single dose of oral nattokinase at 2000 fibrinolytic units, blood fibrin/fibrinogen degradation product levels were significantly increased 4 hours after nattokinase administration, confirming elevation of thrombolysis and anticoagulation profiles ¹⁵. Hsia’s study ⁵⁸ supported nattokinase as a useful fibrinolytic/anticoagulant agent to reduce the risk of thrombosis and cardiovascular disease in humans.

Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism ⁷⁰. Thrombolytic/fibrinolytic therapy is used in myocardial infarction, cerebral infarction, and, on occasion, in massive pulmonary embolism. Fibrinolytic therapy can, in many circumstances, reduce mortality. As a result, the use of such treatments has increased rapidly in recent years ⁷¹. Commonly used commercial thrombolytic agents, such as plasminogen activators, streptokinase, and anisoylated plasminogen streptokinase-activator complex, all come with serious drawbacks and adverse effects. These thrombolytic drugs are usually expensive, have a short half-life after intravenous administration, and lead to uncontrollable acceleration of fibrinolysis and hemorrhaging. To overcome these risks, a safer thrombolytic agent such as nattokinase is needed for the treatment of thrombolytic disorders or cardiovascular disease ⁶⁰.

Antiplatelet and anticoagulant effects

Low-dose aspirin (85-100 mg daily), as a potent anticoagulant agent, is widely used for the prevention of heart attacks, stroke, and atherothrombotic diseases. Aspirin exerts its antiplatelet action by inhibiting cyclooxygenase (COX) and subsequently reducing the synthesis of thrombogenic thromboxane A2 (TXA2) in platelets. However, the long-term use of aspirin comes with serious gastrointestinal side effects and bleeding ⁷². In a study comparing the antiplatelet effects of nattokinase and aspirin, nattokinase was shown to display excellent antiplatelet aggregation and antithrombotic activities in vitro and in vivo, inhibiting thromboxane B2 formation from collagen-activated platelets ¹⁰. Wang et al ⁷³ found that nattokinase decreased fibrinogen levels in a cerebral ischemic model and concluded that this was mediated by a pathway similar to that of aspirin. Natto showed an excellent inhibitory effect on platelet aggregation induced by adenosine 5ʹ diphosphate and collagen ⁷⁴. In addition, nattokinase was found to have positive in vitro hemorheological effects by decreasing red blood cell aggregation and low-shear viscosity ⁷⁵.

All the above data suggest that nattokinase could be a good candidate, without any obvious adverse effects, for the improvement of blood flow and possibly superior to aspirin.

Anti-atherosclerotic and lipid-lowering effects

The underlying pathological change shared by many cardiovascular diseases is atherosclerosis, which is the primary cause of heart disease and stroke ⁷⁶. Therefore, drugs that have anti-atherosclerotic effects would have broad clinical relevance; however, these types of drugs are difficult to come by. Nattokinase would appear to be one of those drugs that have such promising anti-atherosclerotic and lipid-lowering effects.

A number of animal studies exploring nattokinase as an anti-atherosclerotic agent have demonstrated that dietary natto extract supplementation suppresses intimal thickening in rats when compared with the control group ⁷⁷. The suppression of intimal thickening after vascular injury may be attributable to the enhanced thrombolytic activities of nattokinase ⁶⁸. There was a striking difference in intimal thickening between the control group and natto fed group where the animals were fed the natto extract or nattokinase for 3 weeks before the injury. Both nattokinase and the natto extract suppressed intimal thickening in rats with endothelial injury. Although Chang et al ⁷⁸ believed that the natto extract suppressed intimal thickening through a synergistic effect attributed to its antioxidant and antiapoptotic properties, other study demonstrated that nattokinase prevented arteriosclerosis by its direct antioxidant effect leading to reduced lipid peroxidation and improved lipid metabolism (inhibition of low-density lipoprotein [LDL or “bad” cholesterol] oxidation) ⁷⁹. When used in combination with red ginseng, nattokinase was found to reduce aortic plaque area in hypercholesterol diet–fed rabbits ⁸⁰.

In a recent clinical study conducted in a laboratory ⁹, daily nattokinase supplementation was an effective way to suppress the progression of atherosclerosis in patients with atherosclerotic plaques. Following nattokinase treatment for 26 weeks, there was a significant reduction in common carotid artery intima-media thickness and carotid plaque size when compared with the baseline before treatment. The carotid plaque size and ommon carotid artery intima-media thickness reduced from 0.25 ± 0.12 cm² to 0.16 ± 0.10 cm² and from 1.13 ± 0.12 mm to 1.01 ± 0.11 mm, respectively. The reduction in the nattokinase group was more significant than that in the group treated with simvastatin (daily dose of 20 mg). The study data suggested that nattokinase was a better alternative to statins, a commonly used drug to reduce atherosclerosis, and furthermore, nattokinase could be a viable alternative therapy for cardiovascular attack and stroke in patients ⁹.

The underlying mechanisms by which nattokinase suppresses atherosclerosis are not known. Early studies indicated that nattokinase enhanced thrombolytic activities ⁶⁸. Available data suggest that the anti-atherosclerotic effect of nattokinase is due to the collective effects of the combination of antithrombotic, anticoagulant, antioxidant, and lipid-lowering effects of nattokinase or natto extract containing nattokinase ⁹.

In addition to its anti-atherosclerotic effects, nattokinase or natto extract also has a favourable effect on lipids. Using nattokinase or natto extract containing nattokinase, studies from various laboratories ⁸⁰ confirmed that nattokinase has a hypolipidemic effect and can significantly reduce the increased serum triglycerides, total cholesterol, and LDL cholesterol (“bad” cholesterol) levels in animal models. Our studies found that in patients with hyperlipidemia, nattokinase treatment (26 weeks at 6500 fibrinolytic units) reduced total cholesterol, LDL cholesterol (“bad” cholesterol) and triglycerides. In addition, nattokinase increased the level of high-density lipoprotein cholesterol (HDL-C or “good cholesterol) ⁹. However, in a small pilot study, Wu et al ⁵⁵ observed a decrease in serum cholesterol, LDL-C, and HDL-C in the nattokinase treatment group following 8 weeks of treatment at a dose of 4000 fibrinolytic units, although the difference was not statistically significant. The insignificant change in serum lipid level observed by Wu et al ⁵⁵ may be related to the relatively low dosages used and a shorter treatment period. Considering the dosages used in the laboratory studies, showing that hypolipidaemic effects were quite high (eg, Xie et al ⁸¹ used a daily dose between 90 and 360 mg/kg in their rats, whereas Wu et al ⁵⁵ used 400 mg daily in their patients), the lipid-lowering action of nattokinase possibly requires a relatively higher dose or longer treatments.

Nattokinase for high blood pressure

Natto has been observed to have a beneficial effect on cardiovascular diseases by lowering blood pressure. In an in vitro study, it was found that natto contained relatively strong inhibitors that suppress angiotensin-converting enzyme (ACE), a key enzyme responsible for the production of a hypertensive peptide hormone, angiotensin II, in the renin-angiotensin system ⁸².

In 2008, Kim et al ⁵⁴ conducted the first randomised double-blinded placebo-controlled trial to investigate the effects of nattokinase supplementation on blood pressure in prehypertension or stage 1 hypertension subjects. Oral administration of nattokinase for 8 weeks resulted in a reduction of both systolic and diastolic blood pressure (net changes were −5.55 and −2.84 mm Hg, respectively). The results suggested that nattokinase could play a role in the prevention and treatment of hypertension ⁵⁴. Recently, a study by Jensen et al ⁵³ suggested that nattokinase consumption for 8 weeks was associated with beneficial changes to blood pressure in patients having hypertension. This is consistent with several laboratory studies demonstrating effective reduction of blood pressure in spontaneous hypertensive rats by nattokinase administration ⁸³.

The mechanism by which nattokinase decreased blood pressure in hypertensive conditions is not clear. Jensen et al ⁵³ found that the decline of blood pressure in hypertensive patients in their study was independent of plasma renin activity and the role of ACE in the antihypertensive action of nattokinase is somewhat controversial. Although studies in humans showed that ACE concentrations did not demonstrate a statistically significant difference in patients receiving nattokinase treatment ⁵⁴, other studies using animal models suggested that the antihypertensive action of nattokinase is related to the inhibition of angiotensin I–converting enzyme ⁸⁴. In a study using spontaneously hypertensive rats, nattokinase and its fragments reduced hypertension by different mechanisms ⁸. Nattokinase may decrease blood pressure through cleavage of fibrinogen in plasma, whereas the fragments of nattokinase potentially prevented the elevation of plasma angiotensin II level to suppress hypertension in rats ⁸. Ibe et al ⁸⁵ found that natto significantly decreased blood pressure 4 hours after oral administration in spontaneously hypertensive rats and the ACE inhibition of natto was dose dependent. Natto extracts from B subtilis–fermented pigeon pea also significantly increased ACE inhibitor activity in hypertensive rats ⁸³.

Given the significant side effects associated with the long-term use of antihypertensive drugs ⁸⁶, nattokinase could be a promising alternative for the management of hypertension in patients with cardiovascular disease. Thus, daily use of nattokinase could be a successful strategy for the treatment of hypertension ⁸⁷.

Neuroprotective effects

Nattokinase is capable of degrading amyloid fibrils at neutral pH and normal body temperature, suggesting a role in the treatment of amyloid-related diseases such as Alzheimer disease ⁸⁸. The ability of nattokinase to dissociate amyloid suggested that nattokinase was a potential drug candidate for amyloid-related disorders and this was confirmed in a recent study involving both in vivo and in vitro models ⁸⁹. Oral administration of nattokinase in the rat model of Alzheimer’s disease demonstrated a positive effect in modulation of specific factors in the Alzheimer’s disease pathway ²⁶. In a rat model of cognitive deficits of Alzheimer’s disease induced by intoxification of colchicine, nano-nutraceuticals containing nattokinase were demonstrated to enhance the impaired learning and memory capability and to be effective inhibitors in the suppression of beta-amyloid and BACE-1 activity, thus suggesting a neuroprotective efficacy of nattokinase ⁹⁰. Ahmed et al ⁹¹ demonstrated that nattokinase, at a dose of 360 fibrinolytic units/kg, significantly decreased cholinesterase activity, TGF-β, IL-6, and p53 levels accompanied by a significant increase in Bcl-2 levels as compared with an untreated Alzheimer’s disease control group. Their data suggested that the neuroprotective effect of nattokinase was due to its proteolytic, anti-inflammatory, and antiapoptotic effects.

In one of the early clinical studies describing the role of nattokinase in the prevention of stroke progression in patients with acute ischaemic stroke, the authors demonstrated a clear neuroprotective effect in patients ⁵². The neuroprotective effects of nattokinase were demonstrated in a photothrombotic stroke mouse model. Ahn et al ⁹² suggested that the neuroprotective effect in the ischemic brain was induced through improved blood flow by inhibiting platelet aggregation and thrombus formation by nattokinase, as reported in a conference abstract. Oral intake of nattokinase was also shown to confer neuroprotective effects against focal cerebral ischaemia as evidenced by reduced infarct volume in gerbils through enhanced fibrinolytic activity ⁷³. Regarding the mechanism by which nattokinase protects the brain in ischemic stroke, a study by Ji et al ²⁵ showed that the neuroprotective effect of nattokinase was associated with its antiplatelet activity, antiapoptotic effect, its ability to relax vascular smooth muscle, and its protection of endothelial cells through increased fibrinolytic activity and facilitating spontaneous thrombolysis.

Cardiovascular health is closely linked to brain health. There is a strong causal association between cardiovascular disease risk factors with the incidence of cognitive decline and Alzheimer’s disease ⁹³. Therefore, neuroprotective effects of drugs used in patients with cardiovascular disease have great potential and would add benefits to patients’ overall outcome. Despite more than 100 neuroprotective agents demonstrating neuroprotective effects on focal ischemic stroke in recent preclinical studies, none has proven to be beneficial in clinical studies ⁹⁴. Hence, more effective drugs, with proven neuroprotective actions, for the management of cerebrovascular diseases, such as ischaemic heart disease and stroke, are urgently needed.

Nattokinase dosage

There is no set effective dosing for nattokinase, but nattokinase 100 mg (equivalent to 2,000 fibrinolytic units [FU]) taken up to 3 times a day, has been used in some studies. Avoid nattokinase in patients with ischemic stroke, peptic ulcer, and coagulation disorders, as well as pre- and post-surgery.

Nattokinase dangers

Information regarding nattokinase safety and efficacy during pregnancy and breastfeeding is lacking. Potential drug interactions and contraindications to the use of nattokinase in humans are not currently known ⁷. Nattokinase has pharmacologic effects that could increase the risk of bleeding with anticoagulants and antiplatelet agents. High concentrations of vitamin K2 (menaquinone) in natto can reduce the international normalized ratio (INR) with warfarin; this may also occur with nattokinase supplements if vitamin K2 (menaquinone) is not removed during the production process. Small short-term trials evaluating the effect of nattokinase reported no adverse reactions. There is a theoretical risk of bleeding, based on a case report of acute cerebellar hemorrhage in a patient with a history of ischemic stroke. Thrombosis was reported after substitution of nattokinase for warfarin in a patient with a mechanical aortic valve. Rare cases of late-onset anaphylaxis with natto have been attributed to poly (gamma-glutamic acid), a product of the fermentation process that may be present in nattokinase supplements. There is one report of a patient concurrently using aspirin and nattokinase (400 mg daily), experiencing an acute cerebellar hemorrhage (bleeding in the cerebellum of the brain) ⁹⁵. In addition, multiple microbleeds were demonstrated on brain magnetic resonance images suggesting that nattokinase may increase risk of intracerebral hemorrhage (bleeding within the brain tissue) in patients who have bleeding-prone cerebral microangiopathy and are taking aspirin concurrently ⁹⁵. In another report, a patient developed a a blood clot (thrombus) in a mechanical valve after nearly a year of nattokinase use without warfarin and underwent a successful repeat valve replacement ⁹⁶. Use of multiple drugs concurrently is common in patients with cardiovascular disease. Therefore, it is particularly important to elucidate the potential possible interactions of nattokinase with other drugs acting on the cardiovascular system.

Given the fact that serine proteases (urokinase and tissue-plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1]), currently in clinical use for stroke patients, have been implicated in tumor growth and metastasis ⁹⁷, it is necessary to design studies to evaluate the potential carcinogenic effects, and effects on cell invasiveness, of nattokinase use in in vitro and in vivo model systems, and to ascertain the presence of any cardiotoxicity associated with this compound ⁷.

Nattokinase side effects

The safety of nattokinase has been comprehensively evaluated in several Good Laboratory Practice  compliant studies in rodents and in human volunteers ⁵⁷. Nattokinase was found to be nonmutagenic (not causing genetic changes) and nonclastogenic (not causing chromosomal changes) in vitro, and no adverse effects were observed in 28-day and 90-day subchronic toxicity studies conducted in rats at doses up to 1000 mg/kg/day, which is 100 times higher than the usual dose used in humans. In human volunteers, no adverse effects were observed following 4 weeks of nattokinase consumption at a daily dose of 10 mg/kg for 28 days ⁵⁷. No sign of toxicity was observed in the Ames test, the bone marrow cell micronucleus tests, or the mouse sperm abnormality tests following nattokinase treatment. In an acute toxicology study conducted by Fu et al ⁹⁸, no sign of toxicity was observed at daily doses of nattokinase of up to 4 g/kg for a period of 30 days. All these data collectively confirm nattokinase to be a safe product with very little or no toxicologic concerns.

Nattokinase summary

In summary, compared with traditional antithrombotic and antihypertensive drugs, nattokinase is characterised by high safety, low cost, simple production process, oral availability, and long in vivo half-life ⁷. As such, nattokinase is expected to become a new-generation drug for thrombotic disorders or cardiovascular diseases. Although human trials and clinical studies demonstrated the clinical benefits of nattokinase in the clinical settings, there remain a number of limitations. However, further clinical trials are needed to fully examine the prospect of nattokinase as an alternative medication to tPA, aspirin, warfarin, or newer anticoagulants in the management of cardiovascular disease. In the near future, it is possible that patients with cardiovascular disease may need only a single nattokinase pill to replace multiple drugs administered for the prevention and management of cardiovascular disease, including tPA, antihypertensives, statins, aspirin, and warfarin.

There are a few obstacles that remain to be overcome for nattokinase to become more widely accepted as a drug or drug candidate, for cardiovascular diseases and these include establishment of pharmacokinetic evidence of the absorption and metabolism of nattokinase in humans and the requirement for extensive studies to elucidate potential drug interactions between nattokinase and other cardiovascular drugs, which are commonly and concurrently used in the prevention, treatment, and management of cardiovascular disease in affected patients ⁷.

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