Common Name(s): Flite Tabs, Natto-K, Natto, NattoMax, Natural Super Kinase – Spray Dried(NSK-SD), Vein Caps, Cardiokinase, Fermented soybeans, Nattokinase, Subtilisin NAT, Subtilisin natto
Nattokinase is a fibrinolytic enzyme found in natto, a traditional Japanese food. It is produced by Bacillus subtilis (also called Bacillus natto or Bacillus subtilis natto) during the fermentation process that turns boiled soybeans into natto. Similar fibrinolytic enzymes are found in other traditional fermented foods, including chungkook-jang in Korea, douchi in China, thua nao in Thailand, and tempeh in Indonesia.1, 2 Fermentation technology is used to manufacture nattokinase supplements that are formulated into powders, pills, and capsules, alone or with other ingredients.2, 3
The fermentation of soybeans is a common traditional Asian and African culinary practice. Natto is a traditional Japanese food that has been consumed for at least 1,000 years. It is usually served as breakfast with rice, on toast, or as sushi; it is also available as an ice cream flavor. Traditionally, it has been used for heart conditions, to relieve fatigue, and as an antiberiberi agent. In the 1980s, researchers investigating food substances for thrombolytic properties isolated the enzyme nattokinase from natto.1, 3, 4 The first commercial nattokinase product was marketed in Japan in 1998.5 Although it has been marketed as a dietary supplement in many parts of the world since that time, in 2012, Health Canada determined that safety concerns, including the potential for increased bleeding risk, had not been adequately addressed to allow the marketing of nattokinase.6 An application was filed in the European Union for approval of nattokinase as a novel food.7 Nattokinase currently does not have generally recognized as safe (GRAS) status with the US Food and Drug Administration.
Natto has a characteristic smell (possibly because of its pyrazine content), a viscous texture, and a strong, distinct flavor, and has been described as a "vegetable cheese" because of its consistency. Although the name implies that it is a kinase, nattokinase is actually an alkaline serine protease with an amino acid sequence similar to that of subtilisin, which is used in laundry detergents. It contains 275 amino acids and has a molecular weight of 27.7 kDa.2 The enzyme catalyzes the cleavage of proteins to polypeptides and has high substrate specificity for fibrin, with substantial fibrinolytic activity at a pH range of 6 to 12.2 The proteolytic activity of nattokinase is measured in fibrin units (FU).8 A 50 g serving of natto provides 1,500 FU of nattokinase. The enzyme can withstand temperatures of up to 50°C and repeated freezing and thawing, but it is inactive in acidic conditions. Microencapsulated and enteric-coated formulations have been developed to reduce degradation of nattokinase by gastric acid.2
B. subtilis also produces and secretes vitamin K2 (menaquinone-7), bacillopeptidase F (another fibrinolytic enzyme marketed as a dietary supplement), and other proteolytic enzymes during the natto fermentation process.9, 10 Vitamin K2 may be removed from nattokinase supplements in the manufacturing process. Methods have been described to optimize the production of the enzyme, remove vitamin K2, and eliminate the characteristic natto odor from nattokinase products.3, 4, 11, 12, 13, 14, 15
A single-dose study evaluated the pharmacokinetics of oral nattokinase in 11 healthy volunteers.16 Peak serum concentrations were reached at 13.3 ± 2.5 hours after a dose of 2,000 FU. Because nattokinase was detected in the serum with an enzyme-linked immunosorbent assay using a polyclonal antibody that reacts with both nattokinase and metabolites, it is unclear whether the nattokinase detected in this study was biologically active.
Uses and Pharmacology
Fibrinolysis and thrombolysis
In vitro/animal studies
The fibrinolytic action of nattokinase has been studied extensively in in vitro studies. Unlike streptokinase, nattokinase does not act directly on plasminogen. The enzyme appears to cleave plasminogen activator inhibitor type 1, thereby increasing the activity of tissue plasminogen activator and promoting the conversion of plasminogen to plasmin, with a resultant increase in clot lysis. Nattokinase also acts directly on thrombi by lysing crosslinked fibrin. The fibrinolytic action of nattokinase is reportedly 4 times that of plasmin. Using human whole blood exposed to nattokinase, dose-dependent decreases in red blood cell aggregation and low-shear viscosity have also been demonstrated.3, 4, 17, 18, 19
Nattokinase was absorbed across rat intestine. The fibrinolytic and thrombolytic activity of nattokinase has been evaluated in animal experiments that induced thrombi and endothelial injury in the femoral arteries and common carotid artery in rats. Dietary supplementation with nattokinase suppressed intimal thickening, modulated the lysis of mural thrombi, and improved arterial blood flow more effectively than plasmin and elastase. In dogs, oral administration of nattokinase completely dissolved induced clots from major leg veins within 5 hours of administration, whereas the clots in dogs receiving placebo showed no thrombolysis up to 18 hours.17, 20, 21, 22, 23 Two studies evaluated nattokinase in a rat model of inflammation-induced thrombosis using carrageenan injections. In the first study, injection of nattokinase into rat tails before thrombosis shortened the length of tail thrombosis by approximately 15%.24 In the second study, the area of thrombosis was reduced by the administration of nattokinase after thrombosis.25 These studies suggest that nattokinase affects clot formation and resolution.
Limited clinical trials have not produced definitive results regarding the efficacy of nattokinase as a fibrinolytic.4, 26 One trial evaluated the effect of daily intake of nattokinase on the hematological indices of 12 healthy Japanese volunteers and found enhanced fibrinolytic activity. A gradual increase in euglobulin fibrinolytic activity, an increase in fibrin degradation products, and an increase in tissue plasminogen activator were recorded. Data for all subjects were not published.4, 17 An open-label trial evaluated the effect of nattokinase administration over 2 months on healthy volunteers, as well as in patients with cardiovascular risk factors and in patients on dialysis. Decreases in plasma fibrinogen and coagulation factors VII and VIII were observed over time within each group; however, no group effect was established. The sample size (N = 45) was too small to draw firm conclusions from the study.27 Another trial evaluated the preventive action of nattokinase in subjects at risk of DVT during a long airplane flight. Nattokinase, in an unspecified dose combined with pycnogenol, taken 2 hours before and 6 hours into the flight was reported to reduce thrombotic events, as determined by ultrasounds of the venous system. Edema scores were also reduced, possibly due to the diuretic effect of pycnogenol. However, conclusions regarding the fibrinolytic action of nattokinase cannot be drawn from this study because it evaluated a product containing both nattokinase and pycnogenol.4, 28
In vitro/animal studies
Angiotensin-converting enzyme (ACE) was inhibited by nattokinase in an in vitro study.29 ACE inhibition appeared to be mediated by nattokinase peptide fragments and was not related to the proteolytic activity of intact nattokinase.
A study in spontaneously hypertensive rats evaluated the antihypertensive mechanism of action of intact nattokinase and nattokinase peptide fragments.30 Although both the intact enzyme and fragments reduced blood pressure, only the intact nattokinase reduced plasma fibrinogen levels. The intact nattokinase had no effect on the renin-angiotensin system. The nattokinase peptide fragments reduced plasma angiotensin II but had no effect on renin or ACE activity. The authors propose that the fibrinolytic activity of the intact nattokinase reduces blood pressure by reducing blood viscosity; however, the mechanism of the nattokinase peptide fragments is unclear. In a second study, natto powder that contained gamma-aminobutyric acid and nattokinase reduced blood pressure in spontaneously hypertensive rats but not in rats with normal blood pressure.31 Captopril reduced blood pressure more significantly than natto powder.
A double-blind, randomized clinical trial designed to evaluate the hypotensive effect of nattokinase (N = 86) found decreases in systolic and diastolic blood pressure at 8 weeks, but not at 4 weeks, of daily nattokinase administration. The study enrolled patients with prehypertension or mild hypertension with a mean blood pressure of approximately 145/95 mm Hg at baseline. Conflicting results were obtained for plasma renin values.32 A double-blind crossover study compared the effects of nattokinase and bacillopeptidase F on blood pressure in 20 patients with so-called "lifestyle" diseases, including hypertension, hyperlipidemia, and type 2 diabetes.10 The study reported that blood pressure decreased after treatment with bacillopeptidase F but not after nattokinase treatment. The clinical importance of these results is unclear because patients were not hypertensive at baseline. No hypotensive effect was found in a study evaluating the fibrinolytic effect of nattokinase27 or in another study evaluating the effect on lipid profile.33
In an in vitro study, nattokinase degraded amyloid fibrils, suggesting a potential role in the treatment of amyloid-related diseases such as Alzheimer disease.34 In a rat study, nattokinase increased expression of the gene for ADAM10, a protein that reduces the effects of the amyloid precursor protein.35 In theory, increasing ADAM10 activity may have a future role in managing Alzheimer disease.
Ex vivo studies suggest that nattokinase may have antiplatelet activity. Nattokinase inhibited collagen- and thrombin-induced platelet aggregation in a study using rabbit platelets.36 Nattokinase appeared to inhibit thromboxane A2 production by activated platelets. In another study, nattokinase increased cyclic adenosine monophosphate within rat platelets, which inhibits platelet aggregation.37 In human platelets, nattokinase appeared to inhibit mobilization of calcium stores within platelets in response to platelet activation by thrombin.
A double-blind, randomized clinical trial designed to evaluate the effect of nattokinase in hyperlipidemia found changes in triglycerides and high-density lipoprotein from baseline, but no differences compared with placebo could be demonstrated.33 In a study evaluating the fibrinolytic effect of nattokinase, no effect on the lipid profile was found.27 In a crossover comparison study with bacillopeptidase F, 4 weeks of treatment with nattokinase had no effect on the lipid profile.10
In an experiment conducted in rabbits, intravitreal nattokinase induced posterior vitreous detachment via hydrolysis of collagen fibers; however, studies in clinical applications in humans as an alternative to surgery are lacking.38
Pregnancy / Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
The antithrombotic, fibrinolytic, and antiplatelet activity observed with nattokinase in in vitro and animal studies raises concerns that it may increase the risk of bleeding when administered with anticoagulants and antiplatelet agents.20, 25, 37 In one unpublished study, 12 patients hospitalized for ischemic stroke who were receiving heparin and low-dose aspirin or clopidogrel also received nattokinase 6,000 FU/day for 7 days.7, 8 Coadministration of nattokinase reportedly increased bleeding time and clotting time and decreased prothrombin time, thromboplastin time, and D-dimer levels. Three unspecified temporary adverse reactions were reported. In another unpublished study, nattokinase 1,700 FU daily was given to 30 patients treated with warfarin for 26 weeks.7, 8 Coadministration of nattokinase reportedly stabilized INRs, but details were too insufficient for evaluation.
Patients treated with warfarin should avoid consuming natto because it can decrease the INR.9, 39 Substantial and sustained increases in serum vitamin K2 are attributed to high concentrations of the vitamin in natto and the long half-life of vitamin K2. In addition, ingested B. subtilis can continue to produce vitamin K2 in the gut for up to a week after natto consumption. Washing and boiling natto before eating may prevent sustained increases in vitamin K2 serum concentrations, as well as reducing B. subtilis recovery from feces.40 Vitamin K2 is removed from some nattokinase supplements to eliminate this concern.
Clinical trials evaluating the effect of nattokinase that report no adverse reactions enrolled small numbers of patients for up to 7 months.6, 10, 17, 27, 28, 32, 39 In a 4-week trial, nattokinase had no substantial effect on laboratory tests for hematologic, renal, and hepatic function. Small increases in hematocrit, platelet count, and serum cholinesterase remained within the normal range.10
The potential for increased bleeding risk with nattokinase has not been clearly substantiated. A case report described acute cerebellar hemorrhage in a 52-year-old woman with a history of ischemic stroke. Although the patient was taking daily aspirin and commenced nattokinase at 400 mg daily, causality cannot be established because of her history.41 However, due to the theoretical risk of bleeding, nattokinase should not be taken by patients with ischemic stroke, peptic ulcer, or coagulation disorders; by those undergoing concomitant anticoagulant therapy; or before or after surgery. Given that the vitamin K2 in natto may offset potential bleeding risk, Health Canada raised a concern that removal of vitamin K2 from nattokinase supplements could theoretically increase bleeding risk.6 Current safety data for nattokinase supplements does not address this concern.
A case report illustrates the potential harm of replacing an anticoagulant with nattokinase. A patient with a mechanical aortic valve developed thrombosis requiring valve replacement approximately a year after he substituted nattokinase 100 mg/day for warfarin.42
Natto can rarely cause late-onset anaphylaxis, with symptom onset occurring 4 to 15 hours after ingestion.43, 44 Skin testing has implicated poly (gamma-glutamic acid), a product of the fermentation process, as the cause. Although the poly (gamma-glutamic acid) content can be reduced in the manufacturing process, patients with a history of hypersensitivity reactions to natto should avoid nattokinase supplements.15
A formulation of nattokinase is reported by the manufacturer to be nonmutagenic in the Ames test using 5 strains of bacteria, as well as in a cell-based chromosomal aberration study conducted in CHL/IU cells.8 It was nontoxic in rodent studies that administered doses up to 1,000 mg/kg/day for up to 90 days. The LD50 in a rodent study was more than 20,000 FU/kg (more than 1,000 mg/kg).
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