Health Care Professional Information

Common Name

Natto extract, fermented soybeans

Clinical Summary

Nattokinase is an extracelluar enzyme secreted by the bacterium Bacillus subtilis, used to ferment boiled or steamed soybeans resulting in a preparation called nattō.
Nattō has been consumed as food in Japan for several centuries.
Nattokinase is also available as a supplement and is most known for its fibrinolytic and thrombolytic effects. A few studies have explored its antihypertensive and amyloid-plaque degrading abilities (1) (2) (3) (4) (5).

Nattokinase decreases platelet aggregation and thrombus formation in a dose-dependent fashion both in vitro and in vivo (6) (7). Reduced intimal thickening  was observed in the femoral artery of rats that were fed a diet containing nattō (8).
In a randomized, double-blind, placebo-controlled human trial, nattokinase capsules reduced diastolic and systolic blood pressure in pre-hypertensive patients (3).

The observation that nattokinase degrades amyloid plaques (1) (9) led to an interest in exploring it as a treatment for Alzheimer's disease, which is characterized by accumulation of amyloid plaques.

Nattokinase has also been promoted as an alternative anticancer treatment based on the notion that it can help dissolve the fibrin coating around a tumor, and increase oxygen supply in the blood to inhibit cancer cell growth. However, these mechanisms have not been proven in humans.

Theoretically, nattokinase may increase the risk of bleeding when used with anticoagulant, antiplatelet and fibrinolytic drugs.
Raw nattō contains high levels of vitamin K that may interfere with the action of warfarin (15).

Food Sources

Nattō (soybeans fermented wih B. subtilis)

Purported Uses
  • Antithrombotic
  • Fibrinolytic
  • Alzheimer's disease
  • Hypertension
  • Cancer treatment
Mechanism of Action

In vitro studies show that nattokinase decreases clot formation by cleaving and inactivating the plasminogen activator inhibitor (PAI) via proteolysis at P1-P1’ peptide bond. PAI is a key inhibitor of tissue plasminogen activator (tPA) that converts plasminogen to plasmin. PAI inactivation allows for greater tPA activity and increased lysis of clots (10) (11). In the absence of PAI, nattokinase affects direct proteolysis of fibrin; however, this effect is less than the protelysis achieved by the PAI-mediated pathway (2). The fibrinolytic activity of nattokinase is estimated to be four fold that of plasmin (12).

Nattokinase is currently being evaluated for its potential as an amyloid plaque-degrading agent. Low doses of nattokinase have been shown to increase expression of the ADAM10 gene, which belongs to a family of proteinases that degrade the amyloid precursor protein (APP). The upregulation of ADAM10 may shift the amyloidogenic pathway to the non-amyloidogenic pathway. This activity may be used as a method to prevent amyloid plaque accumulation that characterizes Alzheimer's disease (9).

Pharmacokinetics

Nattokinase is active when consumed orally. Preliminary studies show detectable serum levels of nattokinase metabolites for 8-12 hours following oral administration (5). However, intact enzymes were not easily detectable, and require further studies to determine the metabolism (13).

Warnings

Theoretically, nattokinase can cause an existing clot to dislodge due to its fibrinolytic property, resulting in a stroke or embolus at a distal location. Patients with a history of deep vein thrombosis should avoid of use nattokinase (5).

Contraindications

Patients with coagulation disorders and those currently undergoing anticoagulant, fibrinolytic, or antithrombotic treatments should avoid nattokinase.

Adverse Reactions

Adverse reactions have not been reported.

Herb-Drug Interactions
  • Aspirin: Nattokinase may increase the risk of intracerebral hemorrhage (14).
  • Anticoagulant/antiplatelet/fibrinolytic drugs: Theoretically, nattokinase may increase the risk of bleeding.
  • Warfarin:  Nattō is rich in vitamin K (also, following consumption, the Bacillus subtilis bacteria in natto continue synthesizing vitamin K in the intestine), which can reduce the effects of warfarin (15).
Herb Lab Interactions
  • May prolong PT, PTT and INR (8)
  • May decrease fibrinogen (12)
Literature Summary and Critique

Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res. 2008 Aug;31(8):1583-8.
This randomized, double-blind, placebo-controlled trial was conducted to examine the effects of nattokinase on blood pressure. Eighty-six patients with high blood pressure received nattokinase (2,000 fibrinolytic units/capsule) or placebo for 8 weeks. When compared with the control group, the treatment group had net changes in systolic and diastolic blood pressures of -5.55 mm Hg and -2.84 mm Hg respectively. The authors concluded that nattokinase intake may help treat and prevent hypertension.

Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs: the LONFLIT-FLITE randomized, controlled trial. Angiology. 2003 Sep-Oct;54(5):531-9.
This study tested the role of nattokinase in preventing deep vein thrombosis (DVT). DVT formation was evaluated in 186 participants in flights traveling across the Atlantic ocean. Ninety-two participants were shown exercises to reduce DVT, and 94 participants were shown the same exercises and were also given a supplement containing pycnogenol and nattokinase. Both groups were evaluated for DVTs before and after their flights. No DVTs formed in the exercise + supplement group, whereas 5 participants in the exercise-only group developed DVTs. Nattokinase may help prevent DVT formation.
However, this is not an FDA-approved treatment. More studies are required to evaluate the incidence and benefits of using this supplement for prophylaxis.

Dosage (Inside MSKCC Only)
This field is only visible to only OneMSK users.
References
  1. Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto. J Agric Food Chem. Jan 2009;57(2):503-508.
  2. Tai MW, Sweet BV. Nattokinase for prevention of thrombosis. Am J Health Syst Pharm. Jun 2006;63(12):1121-1123.
  3. Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res. Aug 2008;31(8):1583-1588.
  4. Hattori T, Ohishi H, Yokota T, Ohoami H, Watanabe K. Antioxidative effect of crude antioxidant preparation from soybean fermented by Bacillus natto. LWT - Food Science and Technology. 1995;28(1):135-138.
  5. Milner M, Makise K. Natto and Its Active Ingredient Nattokinase: A Potent and Safe Throbmolytic Agent. Alternative & Complementary Therapies. 2002;8(3):157.
  6. Jang JY, Kim TS, Cai J, et al. Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Lab Anim Res. Dec 2013;29(4):221-225.
  7. Fujita M, Hong K, Ito Y, Fujii R, Kariya K, Nishimuro S. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat. Biol Pharm Bull. Oct 1995;18(10):1387-1391.
  8. Kotb E. The biotechnological potential of fibrinolytic enzymes in the dissolution of endogenous blood thrombi. Biotechnol Prog. May 2014;30(3):656-672.
  9. Fadl NN, Ahmed HH, Booles HF, Sayed AH. Serrapeptase and nattokinase intervention for relieving Alzheimer's disease pathophysiology in rat model. Hum Exp Toxicol. Jul 2013;32(7):721-735.
  10. DeDea L. The antiplatelet effects of aspirin; nattokinase as a blood thinner. JAAPA. December 2010;23(12):13.
  11. Urano T, Ihara H, Umemura K, et al. The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis Cleaves and inactivates plasminogen activator inhibitor type 1. J Biol Chem. Jul 2001;276(27):24690-24696.
  12. Wang J-M, Chen H-Y, Cheng S-M, Cheng S-H, Yang L-L, Cheng F-C. Nattokinase reduces brain infarction, fribinogen, and activated paritall thromboplastin time against cerebral ischemia-reperfusion injury. Journal of Food & Drug Analysis. 2012;20(3):686.
  13. Ero MP, Ng CM, Mihailovski T, Harvey NR, Lewis BH. A pilot study on the serum pharmacokinetics of nattokinase in humans following a single, oral, daily dose. Altern Ther Health Med. 2013 May-Jun 2013;19(3):16-19.
  14.  Chang YY, Liu JS, Lai SL, Wu HS, Lan MY. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds. Intern Med. 2008;47(5):467-469.
  15. Homma K, Wakana N, Suzuki Y, et al. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol (Tokyo). Oct 2006;52(5):297-301.

Consumer Information

How It Works

Bottom Line: Nattokinase may help prevent clot formation and reduce blood pressure. It has not been tested as a cancer treatment in humans.

Nattokinase is an enzyme produced from nattō, a traditional Japanese food made from soybeans fermented with the bacterium, Bacillus subtilis.  It can break down fibrin in the blood that forms clots.  Studies in humans suggest that nattokinase can reduce high blood pressure and may benefit patients with Alzheimer’s disease. Although nattokinase has been promoted as an alternative anticancer treatment, clinical studies have not been conducted to show that it is effective.
Nattokinase may increase the risk of bleeding in patients when used with “blood thinning” drugs. 

Purported Uses
  • Antithrombotic
    A few studies have shown that nattokinase has the ability to prevent deep vein thrombosis.
  • Hypertension
    Nattokinase has been shown in clinical studies to reduce hypertension.
  • Alzheimer’s disease
    Studies using animal models have shown that nattokinase can degrade amyloid plaques. Human studies have not been conducted.
  • Cancer treatment
    Although nattokinase is promoted as an alternative cancer treatment, clinical data of its effectiveness are lacking.
Research Evidence

Hypertension:
A study involving 86 participants evaluated the ability of nattokinase to lower blood pressure. Forty-two participants were given placebo, and 44 were given a nattokinase supplement. All the participants were told to maintain their normal diet and lifestyle. The results showed that the group which received nattokinase had larger decreases in both systolic and diastolic blood pressure.

Deep Vein Thrombosis:
Another clinical trial was done to find out if nattokinase can help prevent deep vein thrombosis (DVT). DVTs are clots usually found in the lower legs that can dislodge and travel to the lungs or brain resulting in life threatening effects. DVT formation was evaluated in 186 participants traveling from New York to London (or vice versa). Ninety-two participants were shown exercises to reduce DVT formation, and 94 others were shown the same exercises and also given Flite tablets which contained nattokinase. Both groups were evaluated for DVTs before and after their flights. No DVTs formed in the group that received Flite tablets, whereas 5 people in the exercise-only group developed DVTs. Nattokinase may help prevent DVT formation.

Patient Warnings

Theoretically, nattokinase can cause an existing clot to dislodge, resulting in a stroke or embolus at a distal location. Patients with a history of deep vein thrombosis should avoid of use nattokinase.

Do Not Take If
  • You have coagulation disorders or are currently using an anticoagulant drug.
  • You take aspirin daily because nattokinase may increase its effects and lead to excessive bleeding.
Side Effects
  • May increase the risk of bleeding

E-mail your questions and comments to aboutherbs@mskcc.org.