Nattokinase

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Nattokinase

Common Names

  • Natto extract
  • Fermented soybeans

For Patients & Caregivers

How It Works

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. Lab studies suggest it can break down fibrin in the blood that forms clots or affect some factors that characterize Alzheimer’s disease. Human studies are limited, and suggest nattokinase may reduce high blood pressure. Although nattokinase has been promoted as an alternative anticancer treatment, clinical studies have not been conducted.

Nattokinase may increase the risk of bleeding in patients when used with blood-thinning drugs.

Purported Uses
  • To prevent blood clots
    Preliminary studies suggest that nattokinase may prevent deep vein thrombosis.
  • To reduce high blood pressure
    Preliminary studies suggest nattokinase may lower blood pressure.
  • Alzheimer’s disease
    Although animal models suggest nattokinase may 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.
Patient Warnings

Theoretically, nattokinase can cause an existing clot to dislodge, resulting in a stroke or embolus at a distant 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: Nattokinase may increase its effects and lead to excessive bleeding.
Side Effects
  • May increase the risk of bleeding when used with blood-thinning drugs

Case Report

  • Shortness of breath, mild chest pain, and blood clot: Causing a patient to undergo a repeat valve replacement after self-substituting nattokinase for warfarin for a long period of time.
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For Healthcare Professionals

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 effects on prevention and treatment of clots and to improve blood circulation.

Preliminary studies have explored its antithrombotic and amyloid-plaque degrading abilities (1) (2) (4) (5) (9). 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).

Studies in humans are limited. In a randomized double-blind trial, nattokinase capsules reduced diastolic and systolic blood pressure in prehypertensive patients (3). In subjects with hypercholesterolemia, nattokinase altered hemostatic factors (19).

Nattokinase has 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 bleeding risk 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 with B. subtilis)

Purported Uses
  • Prevent blood clots
  • Hypertension
  • Alzheimer’s disease
  • 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. Upregulation of ADAM10 may shift the amyloidogenic pathway to the non-amyloidogenic pathway. This activity may prevent amyloid plaque accumulation that characterizes Alzheimer’s disease (9).

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 (2).

Adverse Reactions

None reported, but for some it may increase bleeding risk when used with blood-thinning drugs or affect lab results.

Case Report

Dyspnea, mild chest pain, and thrombus on mechanical valve: With long-term self-substitution of nattokinase for warfarin after aortic valve replacement, requiring a repeat valve replacement (16).

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. In a small study of healthy young men, enhanced fibrinolysis and antithrombosis after a single-dose of oral nattokinase occurred, although effects in this group were deemed to be within normal range (17). Laboratory studies indicate that nattokinase is a heparin-binding protein with a binding affinity of approximately 250 nM. The interaction is chain-length dependent, and NK also interfered with heparin interactions with antithrombin and fibroblast growth factors (18).
  • Warfarin: Nattō is rich in vitamin K. In addition, Bacillus subtilis bacteria in natto continue synthesizing vitamin K in the intestine following consumption, which can reduce the effects of warfarin (15).
Herb Lab Interactions
  • May prolong PT, PTT, INR, and C/EPI CT (8) (19)
  • May decrease fibrinogen (12)
Dosage (OneMSK Only)
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 Thrombolytic 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.
  16. Elahi MM, Choi CH, Konda S, et al. Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis. Proc (Bayl Univ Med Cent). Jan 2015;28(1):81-82.
  17. Kurosawa Y, Nirengi S, Homma T, et al. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Sci Rep. Jun 25 2015;5:11601.
  18. Zhang F, Zhang J, Linhardt RJ. Interactions between nattokinase and heparin/GAGs. Glycoconj J. Dec 2015;32(9):695-702.
  19. Yoo HJ, Kim M, Kim M, et al. The effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects. Food Funct. May 22 2019;10(5):2888-2893.
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